Genetic polymorphisms associated with venous thrombosis and statin response, methods of detection and uses thereof

ABSTRACT

The present invention provides compositions and methods based on genetic polymorphisms that are associated with response to statin treatment (particularly for reducing the risk of venous thrombosis). For example, the present invention relates to nucleic acid molecules containing the polymorphisms, variant proteins encoded by these nucleic acid molecules, reagents for detecting the polymorphic nucleic acid molecules and variant proteins, and methods of using the nucleic acid molecules and proteins as well as methods of using reagents for their detection.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. non-provisionalapplication Ser. No. 14/971,503, filed Dec. 16, 2015, which is acontinuation application of U.S. non-provisional application Ser. No.13/847,750, filed Mar. 20, 2013, which is a continuation application ofU.S. non-provisional application Ser. No. 13/286,934, filed Nov. 1,2011, which is a non-provisional application of U.S. provisionalapplication Ser. No. 61/409,434, filed Nov. 2, 2010, the contents ofeach of which are hereby incorporated by reference in its entirety intothis application.

FIELD OF THE INVENTION

The present invention is in the field of disease risk and drug response,particularly genetic polymorphisms that are associated with risk fordeveloping venous thrombosis (VT) and/or response to statins, especiallystatin treatment for the prevention or treatment of VT and relatedpathologies. In particular, the present invention relates to specificsingle nucleotide polymorphisms (SNPs) in the human genome, and theirassociation with risk for developing VT and/or variability inresponsiveness to statin treatment (including preventive treatment) inreducing VT risk between different individuals. The SNPs disclosedherein can be used, for example, as targets for diagnostic reagents andfor the development of therapeutic agents. In particular, the SNPs ofthe present invention are useful for such uses as predicting anindividual's response to therapeutic agents such as evaluating thelikelihood of an individual differentially responding positively tostatins, particularly for the treatment or prevention of VT (includingrecurrent VT), identifying an individual who has an increased ordecreased risk of developing VT (including recurrent VT), for earlydetection of VT, for providing clinically important information for theprevention and/or treatment of VT, for predicting recurrence of VT, andfor screening and selecting therapeutic agents. Methods, assays, kits,and reagents for detecting the presence of these polymorphisms and theirencoded products are provided.

BACKGROUND OF THE INVENTION

The present invention relates to SNPs that are associated with risk fordeveloping venous thrombosis (VT) and/or variability between individualsin their response to statins, particularly for reducing the risk of VT.

VT, which may also be referred to as venous thromboembolism (VTE),includes deep vein thrombosis (DVT) and pulmonary embolism (PE). VT canfurther include a first occurrence of VT (i.e., primary VT) or recurrentVT.

Venous Thrombosis (VT)

The development of a blood clot is known as thrombosis. Venousthrombosis (VT) is the formation of a blood clot in the veins. VT mayalso be referred to as venous thromboembolism (VTE). Over 200,000 newcases of VT occur annually. Of these, 30 percent of patients die withinthree days; one in five suffer sudden death due to pulmonary embolism(PE) (Seminars in Thrombosis and Hemostasis, 2002, Vol. 28, Suppl. 2)(Stein et al., Chest 2002; 122(3):960-962, further describes PE).Caucasians and African-Americans have a significantly higher incidencethan Hispanics, Asians or Pacific Islanders (White, Circulation 107(23Suppl 1):I14-8 Review, 2003).

Several conditions can lead to an increased tendency to develop bloodclots in the veins or arteries (National Hemophilia Foundation, HemAwarenewsletter, Vol. 6 (5), 2001), and such conditions may be inherited(genetic) or acquired. Examples of acquired conditions are surgery andtrauma, prolonged immobilization, cancer, myeloproliferative disorders,age, hormone therapy, and even pregnancy, all of which may result inthrombosis (Seligsohn et al., New Eng J Med 344(16):1222-1231, 2001 andHeit et al., Thromb Haemost 2001; 86(1):452-463). Family and twinstudies indicate that inherited (genetic) causes account for about 60%of the risk for deep vein thrombosis (DVT) (Souto et al., Am J Hum Genet2000; 67(6):1452-1459; Larsen et al., Epidemiology 2003; 14(3):328-332).Inherited causes include polymorphisms in any of several differentclotting, anticoagulant, or thrombolytic factors, such as the factor Vgene (the factor V Leiden (FVL) variant), prothrombin gene (factor II),and methylenetetrahydrofolate reductase gene (MTHFR). Other likelyinherited causes are an increase in the expression levels of the factorsVIII, IX or XI, or fibrinogen genes (Seligsohn et al., New Eng J Med344(16):1222-1231, 2001). Deficiencies of natural anticoagulantsantithrombin, protein C and protein S are strong risk factors for DVT;however, the variants causing these deficiencies are rare, and explainonly about 1% of all DVTs (Rosendaal et al., Lancet 1999;353(9159):1167-1173). The factor V Leiden (FVL) and prothrombin G20210Agenetic variants have been consistently found to be associated with DVT(Bertina et al., Nature 1994; 369(6475):64-67 and Poort et al., Blood1996; 88(10):3698-3703) but still only explain a fraction of the DVTevents (Rosendaal, Lancet 1999; 353(9159):1167-1173; Bertina et al.,Nature 1994; 369(6475):64-67; Poort et al., Blood 1996;88(10):3698-3703). Elevated plasma concentrations of coagulation factors(e.g., VIII, IX, X, and XI) have also been shown to be important riskfactors for DVT (Kyrle et al., N Engl J Med. 2000; 343:457-462; vanHylckama Vlieg et al., Blood. 2000; 95:3678-3682; de Visser et al.,Thromb Haemost. 2001; 85:1011-1017; and Meijers et al., N Engl J Med.2000; 342:696-701, respectively).

About one-third of patients with symptomatic VT manifest pulmonaryembolism (PE), whereas two-thirds manifest deep vein thrombosis (DVT)(White, Circulation 107(23 Suppl 1):I4-8 Review, 2003). DVT is an acuteVT in a deep vein, usually in the thigh, legs, or pelvis, and it is aserious and potentially fatal disorder that can arise as a complicationfor hospital patients, but may also affect otherwise healthy people(Lensing et al., Lancet 353:479-485, 1999). Large blood clots in VT mayinterfere with blood circulation and impede normal blood flow. In someinstances, blood clots may break off and travel to distant major organssuch as the brain, heart or lungs as in PE and result in fatality. Thereis evidence to suggest that patients with a first episode of VT betreated with anticoagulant agents (Kearon et al., New Engl J Med340:901-907, 1999).

VT is a chronic disease with episodic recurrence; about 30% of patientsdevelop recurrence within 10 years after a first occurrence of VT (Heitet al., Arch Intern Med. 2000; 160: 761-768; Heit et al., Thromb Haemost2001; 86(1):452-463; and Schulman et al., J Thromb Haemost. 2006; 4:732-742). Recurrence of VT may be referred to herein as recurrent VT.The hazard of recurrence varies with the time since the incident eventand is highest within the first 6 to 12 months. Although anticoagulationis effective in preventing recurrence, the duration of anticoagulationdoes not affect the risk of recurrence once primary therapy for theincident event is stopped (Schulman et al., J Thromb Haemost. 2006; 4:732-742 and van Dongen et al., Arch Intern Med. 2003; 163: 1285-1293).Independent predictors of recurrence include male gender (McRae et al.,Lancet. 2006; 368: 371-378), increasing patient age and body mass index,neurological disease with leg paresis, and active cancer (Cushman etal., Am J Med. 2004; 117: 19-25; Heit et al., Arch Intern Med. 2000;160: 761-768; Schulman et al., J Thromb Haemost. 2006; 4: 732-742; andBaglin et al., Lancet. 2003; 362: 523-526). Additional predictorsinclude “idiopathic” venous thrombosis (Baglin et al., Lancet. 2003;362: 523-526), a lupus anticoagulant or antiphospholipid antibody(Kearon et al., N Engl J Med. 1999; 340: 901-907 and Schulman et al., AmJ Med. 1998; 104: 332-338), antithrombin, protein C or protein Sdeficiency (van den Belt et al., Arch Intern Med. 1997; 157: 227-232),and possibly persistently increased plasma fibrin D-dimer (Palareti etal., N Engl J Med. 2006; 355: 1780-1789) and residual venous thrombosis(Prandoni et al., Ann Intern Med. 2002; 137: 955-960).

VT and cancer can be coincident. According to clinical dataprospectively collected on the population of Olmsted County, Minn.,since 1966, the annual incidence of a first episode of DVT or PE in thegeneral population is 117 of 100,000. Cancer alone was associated with a4.1-fold risk of thrombosis, whereas chemotherapy increased the risk6.5-fold. Combining these estimates yields an approximate annualincidence of VT in cancer patients of 1 in 200 cancer patients (Lee etal., Circulation. 2003; 107:I-17-I-21). Extrinsic factors such assurgery, hormonal therapy, chemotherapy, and long-term use of centralvenous catheters increase the cancer-associated prethrombotic state.Post-operative thrombosis occurs more frequently in patients with canceras compared to non-neoplastic patients (Rarh et al., Blood coagulationand fibrinolysis 1992; 3:451).

Thus, there is a need for novel genetic markers that are predictive ofpredisposition to VT (as well as response to statin treatment forpreventing VT), particularly for individuals who are unrecognized ashaving a predisposition to developing the disease based on conventionalrisk factors, as well as genetic markers that are predictive ofrecurrent VT in individuals who have already experienced a VT event.Such genetic markers may enable screening of VT in much largerpopulations compared with the populations that can currently beevaluated by using existing risk factors and biomarkers. Theavailability of a genetic test may allow, for example, appropriatepreventive treatments for acute venous thrombotic events to be providedfor high risk individuals (such preventive treatments may include, forexample, statins as well as anticoagulant agents). Moreover, thediscovery of genetic markers associated with VT may provide noveltargets for therapeutic intervention or preventive treatments.

HMG-CoA Reductase Inhibitors (Statins)

HMG-CoA reductase inhibitors (statins) can be used for the preventionand treatment of VT, in addition to their use for the prevention andtreatment of other cardiovascular diseases (CVD), particularly coronaryheart disease (CHD) (including coronary events, such as myocardialinfarction (MI), and cerebrovascular events, such as stroke andtransient ischemic attack (TIA)). Reduction of MI, stroke, and othercoronary and cerebrovascular events and total mortality by treatmentwith HMG-CoA reductase inhibitors has been demonstrated in a number ofrandomized, double-blinded, placebo-controlled prospective trials (D. D.Waters, Clin Cardiol 24(8 Suppl):III3-7 (2001); B. K. Singh and J. L.Mehta, Curr Opin Cardiol 17(5):503-11 (2002)). These drugs are thoughtto typically have their primary effect through the inhibition of hepaticcholesterol synthesis, thereby upregulating LDL receptors in the liver.The resultant increase in LDL catabolism results in decreasedcirculating LDL, a major risk factor for cardiovascular disease.

Examples of statins include, but are not limited to, atorvastatin(Lipitor®), rosuvastatin (Crestor®), pravastatin (Pravachol®),simvastatin (Zocor®), fluvastatin (Lescol®), and lovastatin (Mevacor®),as well as combination therapies that include a statin such assimvastatin+ezetimibe (Vytorin®), lovastatin+niacin (Advicor®),atorvastatin+amlodipine besylate (Caduet®), and simvastatin+niacin(Simcor®).

Statins can be divided into two types according to their physicochemicaland pharmacokinetic properties. Statins such as atorvastatin,simvastatin, lovastatin, and cerivastatin are lipophilic in nature and,as such, diffuse across membranes and thus are highly cell permeable.Hydrophilic statins such as pravastatin are more polar, such that theyrequire specific cell surface transporters for cellular uptake. K.Ziegler and W. Stunkel, Biochim Biophys Acta 1139(3):203-9 (1992); M.Yamazaki et al., Am J Physiol 264(1 Pt 1):G36-44 (1993); T. Komai etal., Biochem Pharmacol 43(4):667-70 (1992). The latter statins utilizesa transporter, OATP2, whose tissue distribution is confined to the liverand, therefore, they are relatively hepato-specific inhibitors. B.Hsiang et al., J Biol Chem 274(52):37161-37168 (1999). The formerstatins, not requiring specific transport mechanisms, are available toall cells and they can directly impact a much broader spectrum of cellsand tissues. These differences in properties may influence the spectrumof activities that each statin possesses. Pravastatin, for instance, hasa low myopathic potential in animal models and myocyte cultures comparedto lipophilic statins. B. A. Masters et al., Toxicol Appl Pharmacol131(1): 163-174 (1995); K. Nakahara et al., Toxicol Appl Pharmacol152(1):99-106 (1998); J. C. Reijneveld et al., Pediatr Res39(6):1028-1035 (1996). Statins are reviewed in Vaughan et al., “Updateon Statins: 2003”, Circulation 2004; 110; 886-892.

Evidence from gene association studies is accumulating to indicate thatresponses to drugs are, indeed, at least partly under genetic control.As such, pharmacogenetics—the study of variability in drug responsesattributed to hereditary factors in different populations—maysignificantly assist in providing answers toward meeting this challenge.A. D. Roses, Nature 405(6788):857-865 (2000); V. Mooser et al., J ThrombHaemost 1(7):1398-1402 (2003); L. M. Humma and S. G. Terra, Am J HealthSyst Pharm 59(13):1241-1252 (2002). Associations have been reportedbetween specific genotypes, as defined by SNPs and other geneticsequence variations, and specific responses to cardiovascular drugs. Forexample, a polymorphism in the KIF6 gene is associated with response tostatin treatment (lakoubova et al., “Polymorphism in KIF6 gene andbenefit from statins after acute coronary syndromes: results from thePROVE IT-TIMI 22 study”, J Am Coil Cardiol. 2008 Jan. 29; 51(4):449-55;lakoubova et al., “Association of the 719Arg variant of KIF6 with bothincreased risk of coronary events and with greater response to statintherapy”, J Am Coll Cardiol. 2008 Jun. 3; 51(22):2195; lakoubova et al.,“KIF6 Trp719Arg polymorphism and the effect of statin therapy in elderlypatients: results from the PROSPER study”, Eur J Cardiovasc PrevRehabil. 2010 Apr. 20; and Shiffman et al., “Effect of pravastatintherapy on coronary events in carriers of the KIF6 719Arg allele fromthe cholesterol and recurrent events trial”, Am J Cardiol. 2010 May 1;105(9):1300-5).

There is a need for genetic markers that can be used to predict anindividual's responsiveness to statins. For example, there is a growingneed to better identify people who have a high chance of benefiting fromstatins, and those who have a low risk of developing side-effects. Forexample, severe myopathies represent a significant risk for a lowpercentage of the patient population, and this may be a particularconcern for patients who are treated more aggressively with statins.Furthermore, different patients may have the same risk for adverseevents but are more likely to benefit from a drug (such as statins) andthis may justify use of the drug in those individuals who are morelikely to benefit. Similarly, in individuals who are less likely tobenefit from a drug but are at risk for adverse events, use of the drugin these individuals can be de-prioritized or delayed.

An example of a large trial which analyzed the benefits of statintreatment for reducing the risk of CVD in a large population was theJUPITER Study (described in Ridker et al., “Rosuvastatin to preventvascular events in men and women with elevated C-reactive protein”, NEngl J Med. 2008 Nov. 20; 359(21):2195-207), which demonstrated thatrosuvastatin (Crestor®) significantly reduced the incidence of majorcardiovascular events (including MI, stroke, arterial revascularization,hospitalization for unstable angina, and death from cardiovascularcauses) in a study of 17,802 individuals.

Use of HMG-CoA Reductase Inhibitors (Statins) for Venous Thrombosis (VT)

HMG-CoA reductase inhibitors (statins) can be used to reduce the risk ofVT. For example, the following three case-control studies reported theassociation of statin use with a reduction in the number of VT events:

Simvastatin use was associated with a reduced risk of VT [OR=0.51(0.29-0.91)] in a Group Health Cooperative study of postmenopausalwomen, which contained about 500 DVT cases and 2000 controls of whomabout 5% were statin users (Doggen et al., “HMG CoA reductase inhibitorsand the risk of venous thrombosis among postmenopausal women”, J ThrombHaemost 2004; 2: 700-1).

Current use of statins was associated with a reduced risk of venousthromboembolism [relative risk=0.74 (95% CI, 0.63-0.85)] in a VT studywhich contained 3366 adult patients (18-89 years) diagnosed with primaryincident venous thromboembolism (2310 with venous thrombosis and 1056with pulmonary embolism) (Sorenson et al., “Arterial cardiovascularevents, statins, low-dose aspirin and subsequent risk of venousthromboembolism: a population based case-control study”, J ThrombHaemost 2009; 7: 521-8).

In another study, 154 of 4538 patients used statins (3.3%), as did 354of 5914 control subjects (5.7%). The use of statins [odds ratio (OR)0.45; 95% confidence interval (CI) 0.36-0.56] but not otherlipid-lowering medications (OR 1.22; 95% CI 0.62-2.43), was associatedwith reduced VT risk as compared with individuals who did not use anylipid-lowering medication, after adjustment for age, sex, body massindex, atherosclerotic disease, anti-platelet therapy and use of vitaminK antagonists. Different types and various durations of statin therapywere all associated with reduced VT risk (Ramcharan et al., “HMG-CoAreductase inhibitors, other lipid-lowering medication, antiplatelettherapy, and the risk of venous thrombosis”, J Thromb Haemost 2009; 7:514-20).

Identification of individuals who will respond to statin therapy for theprevention or treatment of VT has the further benefit of enabling theseindividuals to be targeted for statin treatment as an alternative toanticoagulant therapy, which has a high risk of bleeding events, thusproviding a safer course of treatment.

Single Nucleotide Polymorphisms (SNPs)

The genomes of all organisms undergo spontaneous mutations in the courseof their continuing evolution, generating variant forms of progenitorgenetic sequences. Gusella, Ann Rev Biochem 55:831-854 (1986). A variantform may confer an evolutionary advantage or disadvantage relative to aprogenitor form or may be neutral. In some instances, a variant formconfers an evolutionary advantage to individual members of a species andis eventually incorporated into the DNA of many or most members of thespecies and effectively becomes the progenitor form. Additionally, theeffects of a variant form may be both beneficial and detrimental,depending on the environment. For example, a heterozygous sickle cellmutation confers resistance to malaria, but a homozygous sickle cellmutation is usually lethal. In many cases, both progenitor and variantforms survive and co-exist in a species population. The coexistence ofmultiple forms of a genetic sequence segregating at appreciablefrequencies is defined as a genetic polymorphism, which includes singlenucleotide polymorphisms (SNPs).

Approximately 90% of all genetic polymorphisms in the human genome areSNPs. SNPs are single base positions in DNA at which different alleles,or alternative nucleotides, exist in a population. The SNP position(interchangeably referred to herein as SNP, SNP site, SNP locus, SNPmarker, or marker) is usually preceded by and followed by highlyconserved sequences (e.g., sequences that vary in less than 1/100 or1/1000 members of the populations). An individual may be homozygous orheterozygous for an allele at each SNP position. A SNP can, in someinstances, be referred to as a “cSNP” to denote that the nucleotidesequence containing the SNP is an amino acid coding sequence.

A SNP may arise from a substitution of one nucleotide for another at thepolymorphic site. Substitutions can be transitions or transversions. Atransition is the replacement of one purine nucleotide by another purinenucleotide, or one pyrimidine by another pyrimidine. A transversion isthe replacement of a purine by a pyrimidine, or vice versa. A SNP mayalso be a single base insertion or deletion variant referred to as an“indel.” Weber et al., “Human diallelic insertion/deletionpolymorphisms,” Am J Hum Genet 71(4):854-62 (October 2002).

A synonymous codon change, or silent mutation/SNP (terms such as “SNP”,“polymorphism”, “mutation”, “mutant”, “variation”, and “variant” areused herein interchangeably), is one that does not result in a change ofamino acid due to the degeneracy of the genetic code. A substitutionthat changes a codon coding for one amino acid to a codon coding for adifferent amino acid (i.e., a non-synonymous codon change) is referredto as a missense mutation. A nonsense mutation results in a type ofnon-synonymous codon change in which a stop codon is formed, therebyleading to premature termination of a polypeptide chain and a truncatedprotein. A read-through mutation is another type of non-synonymous codonchange that causes the destruction of a stop codon, thereby resulting inan extended polypeptide product. While SNPs can be bi-, tri-, ortetra-allelic, the vast majority of SNPs are bi-allelic, and are thusoften referred to as “bi-allelic markers,” or “di-allelic markers.”

As used herein, references to SNPs and SNP genotypes include individualSNPs and/or haplotypes, which are groups of SNPs that are generallyinherited together. Haplotypes can have stronger correlations withdiseases or other phenotypic effects compared with individual SNPs, andtherefore may provide increased diagnostic accuracy in some cases.Stephens et al., Science 293:489-493 (July 2001).

Causative SNPs are those SNPs that produce alterations in geneexpression or in the expression, structure, and/or function of a geneproduct, and therefore are most predictive of a possible clinicalphenotype. One such class includes SNPs falling within regions of genesencoding a polypeptide product, i.e. cSNPs. These SNPs may result in analteration of the amino acid sequence of the polypeptide product (i.e.,non-synonymous codon changes) and give rise to the expression of adefective or other variant protein. Furthermore, in the case of nonsensemutations, a SNP may lead to premature termination of a polypeptideproduct. Such variant products can result in a pathological condition,e.g., genetic disease. Examples of genes in which a SNP within a codingsequence causes a genetic disease include sickle cell anemia and cysticfibrosis.

Causative SNPs do not necessarily have to occur in coding regions;causative SNPs can occur in, for example, any genetic region that canultimately affect the expression, structure, and/or activity of theprotein encoded by a nucleic acid. Such genetic regions include, forexample, those involved in transcription, such as SNPs in transcriptionfactor binding domains, SNPs in promoter regions, in areas involved intranscript processing, such as SNPs at intron-exon boundaries that maycause defective splicing, or SNPs in mRNA processing signal sequencessuch as polyadenylation signal regions. Some SNPs that are not causativeSNPs nevertheless are in close association with, and therefore segregatewith, a disease-causing sequence. In this situation, the presence of aSNP correlates with the presence of, or predisposition to, or anincreased risk in developing the disease. These SNPs, although notcausative, are nonetheless also useful for diagnostics, diseasepredisposition screening, and other uses.

An association study of a SNP and a specific disorder involvesdetermining the presence or frequency of the SNP allele in biologicalsamples from individuals with the disorder of interest, such as VT, andcomparing the information to that of controls (i.e., individuals who donot have the disorder; controls may be also referred to as “healthy” or“normal” individuals) who are preferably of similar age and race. Theappropriate selection of patients and controls is important to thesuccess of SNP association studies. Therefore, a pool of individualswith well-characterized phenotypes is extremely desirable.

A SNP may be screened in diseased tissue samples or any biologicalsample obtained from a diseased individual, and compared to controlsamples, and selected for its increased (or decreased) occurrence in aspecific pathological condition, such as pathologies related to VT. Oncea statistically significant association is established between one ormore SNP(s) and a pathological condition (or other phenotype) ofinterest, then the region around the SNP can optionally be thoroughlyscreened to identify the causative genetic locus/sequence(s) (e.g.,causative SNP/mutation, gene, regulatory region, etc.) that influencesthe pathological condition or phenotype. Association studies may beconducted within the general population and are not limited to studiesperformed on related individuals in affected families (linkage studies).

Clinical trials have shown that patient response to treatment withpharmaceuticals is often heterogeneous. There is a continuing need toimprove pharmaceutical agent design and therapy. In that regard, SNPscan be used to identify patients most suited to therapy with particularpharmaceutical agents (this is often termed “pharmacogenomics”).Similarly, SNPs can be used to exclude patients from certain treatmentdue to the patient's increased likelihood of developing toxic sideeffects or their likelihood of not responding to the treatment.Pharmacogenomics can also be used in pharmaceutical research to assistthe drug development and selection process. Linder et al., ClinicalChemistry 43:254 (1997); Marshall, Nature Biotechnology 15:1249 (1997);International Patent Application WO 97/40462, Spectra Biomedical; andSchafer et al., Nature Biotechnology 16:3 (1998).

SUMMARY OF THE INVENTION

Exemplary embodiments of the present invention relate to theidentification of SNPs that are associated with risk for developingvenous thrombosis (VT) and/or variability between individuals in theirresponse to statins, particularly for the prevention or treatment of VT.These SNPs are useful for determining risk and/or statin response forprimary and recurrent VT. Accordingly, the polymorphisms disclosedherein are directly useful as targets for the design of diagnostic andprognostic reagents and the development of therapeutic and preventiveagents for use in the diagnosis, prognosis, treatment, and/or preventionof VT, as well as for predicting a patient's response to therapeuticagents such as statins, particularly for the treatment or prevention ofVT.

Based on the identification of SNPs associated with risk for developingVT and/or variability between individuals in their response to statins,particularly for reducing the risk of VT, exemplary embodiments of thepresent invention also provide methods of detecting these variants aswell as the design and preparation of detection reagents needed toaccomplish this task. The invention specifically provides, for example,SNPs associated with VT risk and/or responsiveness to statin treatmentfor reducing VT risk, isolated nucleic acid molecules (including DNA andRNA molecules) containing these SNPs, variant proteins encoded bynucleic acid molecules containing such SNPs, antibodies to the encodedvariant proteins, computer-based and data storage systems containing thenovel SNP information, methods of detecting these SNPs in a test sample,methods of identifying individuals who have an altered (i.e., increasedor decreased) risk of developing VT, methods for determining the risk ofan individual for developing recurrent VT, methods of treating anindividual who has an increased risk for VT, and methods for identifyingindividuals (e.g., determining a particular individual's likelihood) whohave an altered (i.e., increased or decreased) likelihood of respondingto drug treatment (especially statin treatment), particularly drugtreatment of VT, based on the presence or absence of one or moreparticular nucleotides (alleles) at one or more SNP sites disclosedherein or the detection of one or more encoded variant products (e.g.,variant mRNA transcripts or variant proteins), methods of identifyingindividuals who are more or less likely to respond to a treatment suchas statins, methods of screening for compounds useful in the treatmentor prevention of VT, compounds identified by these methods, methods oftreating or preventing VT, etc.

Exemplary embodiments of the present invention further provide methodsfor selecting or formulating a treatment regimen (e.g., methods fordetermining whether or not to administer statin treatment to anindividual having VT, or who is at risk for developing VT in the future,or who has previously had VT, methods for selecting a particularstatin-based treatment regimen such as dosage and frequency ofadministration of statin, or a particular form/type of statin such as aparticular pharmaceutical formulation or statin compound, methods foradministering an alternative, non-statin-based treatment (such aswarfarin or other anticoagulants, e.g., direct thrombin inhibitors suchas dabigatran, or direct factor Xa inhibitors such as rivaroxaban orapixaban) to individuals who are predicted to be unlikely to respondpositively to statin treatment, etc.), and methods for determining thelikelihood of experiencing toxicity or other undesirable side effectsfrom statin treatment, etc. Various embodiments of the present inventionalso provide methods for selecting individuals to whom a statin or othertherapeutic will be administered based on the individual's genotype, andmethods for selecting individuals for a clinical trial of a statin orother therapeutic agent based on the genotypes of the individuals (e.g.,selecting individuals to participate in the trial who are most likely torespond positively from the statin treatment and/or excludingindividuals from the trial who are unlikely to respond positively fromthe statin treatment based on their SNP genotype(s), or selectingindividuals who are unlikely to respond positively to statins based ontheir SNP genotype(s) to participate in a clinical trial of another typeof drug that may benefit them). Further embodiments of the presentinvention provide methods for reducing an individual's risk ofdeveloping VT using statin treatment, including preventing recurrent VTusing statin treatment, when said individual carries one or more SNPsidentified herein as being associated with statin response.

Tables 1 and 2 provides gene information, references to theidentification of transcript sequences (SEQ ID NOS:1-84), encoded aminoacid sequences (SEQ ID NOS:85-168), genomic sequences (SEQ IDNOS:338-500), transcript-based context sequences (SEQ ID NOS:169-337)and genomic-based context sequences (SEQ ID NOS:501-3098) that containthe SNPs of the present application, and extensive SNP information thatincludes observed alleles, allele frequencies, populations/ethnic groupsin which alleles have been observed, information about the type of SNPand corresponding functional effect, and, for cSNPs, information aboutthe encoded polypeptide product. The actual transcript sequences (SEQ IDNOS:1-84), amino acid sequences (SEQ ID NOS:85-168), genomic sequences(SEQ ID NOS:338-500), transcript-based SNP context sequences (SEQ IDNOS:169-337), and genomic-based SNP context sequences (SEQ IDNOS:501-3098) are provided in the Sequence Listing.

In certain exemplary embodiments, the invention provides methods foridentifying an individual who has an altered risk for developing VT(including, for example, a first incidence and/or a recurrence of thedisease, such as primary or recurrent VT), in which the method comprisesdetecting a single nucleotide polymorphism (SNP) in any one of thenucleotide sequences of SEQ ID NOS:1-84, SEQ ID NOS:169-337, SEQ IDNOS:338-500, and SEQ ID NOS:501-3098 in said individual's nucleic acids,wherein the SNP is specified in Table 1 and/or Table 2, and the presenceof the SNP is indicative of an altered risk for VT in said individual.In certain embodiments, the VT is deep vein thrombosis (DVT) orpulmonary embolism (PE). In certain embodiments, the VT is recurrent VT.In certain exemplary embodiments of the invention, SNPs that occurnaturally in the human genome are provided within isolated nucleic acidmolecules. These SNPs are associated with response to statin treatmentthereby reducing the risk of VT, such that they can have a variety ofuses in the diagnosis, prognosis, treatment, and/or prevention of VT,and particularly in the treatment or prevention of VT using statins. Inan alternative embodiment, a nucleic acid of the invention is anamplified polynucleotide, which is produced by amplification of aSNP-containing nucleic acid template. In another embodiment, theinvention provides for a variant protein that is encoded by a nucleicacid molecule containing a SNP disclosed herein.

In further embodiments of the invention, reagents for detecting a SNP inthe context of its naturally-occurring flanking nucleotide sequences(which can be, e.g., either DNA or mRNA) are provided. In particular,such a reagent may be in the form of, for example, a hybridization probeor an amplification primer that is useful in the specific detection of aSNP of interest. In an alternative embodiment, a protein detectionreagent is used to detect a variant protein that is encoded by a nucleicacid molecule containing a SNP disclosed herein. A preferred embodimentof a protein detection reagent is an antibody or an antigen-reactiveantibody fragment. Various embodiments of the invention also providekits comprising SNP detection reagents, and methods for detecting theSNPs disclosed herein by employing the SNP detection reagents. Anexemplary embodiment of the present invention provides a kit comprisinga SNP detection reagent for use in determining whether a human's riskfor VT is reduced by treatment with statins based upon the presence orabsence of a particular allele of one or more SNPs disclosed herein.

In various embodiments, the present invention provides methods forevaluating whether an individual is likely (or unlikely) to respond tostatin treatment (i.e., benefit from statin treatment)), particularlystatin treatment for reducing the risk of VT (including recurrent VT),by detecting the presence or absence of one or more SNP allelesdisclosed herein. In certain embodiments, the VT is DVT or PE. Incertain embodiments, the VT is recurrent VT. The present invention alsoprovides methods of identifying an individual having an increased ordecreased risk of developing VT (including recurrent VT) by detectingthe presence or absence of one or more SNP alleles disclosed herein. Incertain embodiments, the VT is DVT or PE. In other embodiments, a methodfor diagnosis or prognosis of VT by detecting the presence or absence ofone or more SNP alleles disclosed herein is provided.

The nucleic acid molecules of the invention can be inserted in anexpression vector, such as to produce a variant protein in a host cell.Thus, the present invention also provides for a vector comprising aSNP-containing nucleic acid molecule, genetically-engineered host cellscontaining the vector, and methods for expressing a recombinant variantprotein using such host cells. In another specific embodiment, the hostcells, SNP-containing nucleic acid molecules, and/or variant proteinscan be used as targets in a method for screening and identifyingtherapeutic agents or pharmaceutical compounds useful in the treatmentor prevention of VT.

An aspect of this invention is a method for treating or preventing VT(including, for example, a first occurrence and/or a recurrence of thedisease, such as primary or recurrent VT), in a human subject whereinsaid human subject harbors a SNP, gene, transcript, and/or encodedprotein identified in Tables 1 and 2, which method comprisesadministering to said human subject a therapeutically orprophylactically effective amount of one or more agents counteractingthe effects of the disease, such as by inhibiting (or stimulating) theactivity of a gene, transcript, and/or encoded protein identified inTables 1 and 2.

Another aspect of this invention is a method for identifying an agentuseful in therapeutically or prophylactically treating VT, in a humansubject wherein said human subject harbors a SNP, gene, transcript,and/or encoded protein identified in Tables 1 and 2, which methodcomprises contacting the gene, transcript, or encoded protein with acandidate agent under conditions suitable to allow formation of abinding complex between the gene, transcript, or encoded protein and thecandidate agent and detecting the formation of the binding complex,wherein the presence of the complex identifies said agent.

Another aspect of this invention is a method for treating or preventingVT, in a human subject, in which the method comprises:

(i) determining that said human subject harbors a SNP, gene, transcript,and/or encoded protein identified in Tables 1 and 2, and

(ii) administering to said subject a therapeutically or prophylacticallyeffective amount of one or more agents counteracting the effects of thedisease, such as statins.

Another aspect of the invention is a method for identifying a human whois likely to benefit from statin treatment, in which the methodcomprises detecting an allele of one or more SNPs disclosed herein insaid human's nucleic acids, wherein the presence of the allele indicatesthat said human is likely to benefit from statin treatment.

Another aspect of the invention is a method for identifying a human whois likely to benefit from statin treatment, in which the methodcomprises detecting an allele of one or more SNPs that are in LD withone or more SNPs disclosed herein in said human's nucleic acids, whereinthe presence of the allele of the LD SNP indicates that said human islikely to benefit from statin treatment.

Many other uses and advantages of the present invention will be apparentto those skilled in the art upon review of the detailed description ofthe exemplary embodiments herein. Solely for clarity of discussion, theinvention is described in the sections below by way of non-limitingexamples.

DESCRIPTION OF THE TEXT (ASCII) FILES SUBMITTED ELECTRONICALLY VIAEFS-WEB

The following three text (ASCII) files are submitted electronically viaEFS-Web as part of the instant application:

1) File SEQLIST_CD000029ORD.txt provides the Sequence Listing. TheSequence Listing provides the transcript sequences (SEQ ID NOS:1-84) andprotein sequences (SEQ ID NOS:85-168) as referred to in Table 1, andgenomic sequences (SEQ ID NOS:338-500) as referred to in Table 2, foreach gene (or genomic region for intergenic SNPs) that contains one ormore statin response-associated SNPs of the present invention. Alsoprovided in the Sequence Listing are context sequences flanking eachSNP, including both transcript-based context sequences as referred to inTable 1 (SEQ ID NOS:169-337) and genomic-based context sequences asreferred to in Table 2 (SEQ ID NOS:501-3098). The context sequencesgenerally provide 100 bp upstream (5′) and 100 bp downstream (3′) ofeach SNP, with the SNP in the middle of the context sequence, for atotal of 200 bp of context sequence surrounding each SNP. FileSEQLIST_CD000029ORD.txt is 22,428 KB in size, and was created on Oct.31, 2011.

2) File TABLE1_CD000029ORD.txt provides Table 1, which is 172 KB in sizeand was created on Oct. 28, 2011.

3) File TABLE2_CD000029ORD.txt provides Table 2, which is 1,843 KB insize and was created on Oct. 28, 2011.

These three text files are hereby incorporated by reference pursuant to37 CFR 1.77(b)(4).

LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20190300958A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

DESCRIPTION OF THE FIGURE

The FIGURE shows two SNP in the F11 gene significantly associated withstatin response for reducing VT risk: F11 SNP rs2036914 and F11 SNPrs2289252. The FIGURE shows risk of VT according to statin use forrs2289252, rs2036914, and Factor V Leiden genotypes. The odds ratios(shown with 95% confidence intervals) were adjusted for sex and age.

DESCRIPTION OF TABLE 1 AND TABLE 2

Table 1 and Table 2 (both submitted electronically via EFS-Web as partof the instant application) disclose the SNP and associatedgene/transcript/protein information of the present invention. For eachgene, Table 1 provides a header containing gene, transcript and proteininformation, followed by a transcript and protein sequence identifier(SEQ ID NO), and then SNP information regarding each SNP found in thatgene/transcript including the transcript context sequence. For each genein Table 2, a header is provided that contains gene and genomicinformation, followed by a genomic sequence identifier (SEQ ID NO) andthen SNP information regarding each SNP found in that gene, includingthe genomic context sequence.

Note that SNP markers may be included in both Table 1 and Table 2; Table1 presents the SNPs relative to their transcript sequences and encodedprotein sequences, whereas Table 2 presents the SNPs relative to theirgenomic sequences. In some instances Table 2 may also include, after thelast gene sequence, genomic sequences of one or more intergenic regions,as well as SNP context sequences and other SNP information for any SNPsthat lie within these intergenic regions. Additionally, in either Table1 or 2 a “Related Interrogated SNP” may be listed following a SNP whichis determined to be in LD with that interrogated SNP according to thegiven Power value. SNPs can be readily cross-referenced between allTables based on their Celera hCV (or, in some instances, hDV)identification numbers and/or public rs identification numbers, and tothe Sequence Listing based on their corresponding SEQ ID NOs.

The gene/transcript/protein information includes:

-   -   a gene number (1 through n, where n=the total number of genes in        the Table),    -   a gene symbol, along with an Entrez gene identification number        (Entrez Gene database, National Center for Biotechnology        Information (NCBI), National Library of Medicine, National        Institutes of Health) (if Entrez gene information is        unavailable, then Ensembl gene information is used instead)    -   a gene name,    -   an accession number for the transcript (e.g., RefSeq NM number        and/or a Celera hCT identification number) (Table 1 only) (if        RefSeq transcript information is unavailable, then Ensembl        transcript information is used instead),    -   an accession number for the protein (e.g., RefSeq NP number        and/or a Celera hCP identification number) (Table 1 only) (if        RefSeq protein information is unavailable, then Ensembl protein        information is used instead),    -   the chromosome number of the chromosome on which the gene is        located,    -   an OMIM (“Online Mendelian Inheritance in Man” database, Johns        Hopkins University/NCBI) public reference number for the gene,        and OMIM information such as alternative gene/protein name(s)        and/or symbol(s) in the OMIM entry.

Note that, due to the presence of alternative splice forms, multipletranscript/protein entries may be provided for a single gene entry inTable 1; i.e., for a single Gene Number, multiple entries may beprovided in series that differ in their transcript/protein informationand sequences.

Following the gene/transcript/protein information is a transcriptcontext sequence (Table 1), or a genomic context sequence (Table 2), foreach SNP within that gene.

After the last gene sequence, Table 2 may include additional genomicsequences of intergenic regions (in such instances, these sequences areidentified as “Intergenic region:” followed by a numericalidentification number), as well as SNP context sequences and other SNPinformation for any SNPs that lie within each intergenic region (suchSNPs are identified as “INTERGENIC” for SNP type).

Note that the transcript, protein, and transcript-based SNP contextsequences are all provided in the Sequence Listing. The transcript-basedSNP context sequences are provided in both Table 1 and also in theSequence Listing. The genomic and genomic-based SNP context sequencesare provided in the Sequence Listing. The genomic-based SNP contextsequences are provided in both Table 2 and in the Sequence Listing. SEQID NOs are indicated in Table 1 for the transcript-based contextsequences (SEQ ID NOS:169-337); SEQ ID NOs are indicated in Table 2 forthe genomic-based context sequences (SEQ ID NOS:501-3098).

The SNP information includes:

-   -   Context sequence (taken from the transcript sequence in Table 1,        the genomic sequence in Table 2) with the SNP represented by its        IUB code, including 100 bp upstream (5′) of the SNP position        plus 100 bp downstream (3′) of the SNP position (the        transcript-based SNP context sequences in Table 1 are provided        in the Sequence Listing as SEQ ID NOS:169-337; the genomic-based        SNP context sequences in Table 2 are provided in the Sequence        Listing as SEQ ID NOS:501-3098).    -   Celera hCV internal identification number for the SNP (in some        instances, an “hDV” number is given instead of an “hCV” number).    -   The corresponding public identification number for the SNP, the        rs number.    -   “SNP Chromosome Position” indicates the nucleotide position of        the SNP along the entire sequence of the chromosome as provided        in NCBI Genome Build 37.    -   SNP position (nucleotide position of the SNP within the given        transcript sequence (Table 1) or within the given genomic        sequence (Table 2)).    -   “Related Interrogated SNP” is the interrogated SNP with which        the listed SNP is in LD at the given value of Power.    -   SNP source (may include any combination of one or more of the        following five codes, depending on which internal sequencing        projects and/or public databases the SNP has been observed in:        “Applera”=SNP observed during the re-sequencing of genes and        regulatory regions of 39 individuals, “Celera”=SNP observed        during shotgun sequencing and assembly of the Celera human        genome sequence, “Celera Diagnostics”=SNP observed during        re-sequencing of nucleic acid samples from individuals who have        a disease, “dbSNP”=SNP observed in the dbSNP public database,        “HGBASE”=SNP observed in the HGBASE public database, “HGMD”=SNP        observed in the Human Gene Mutation Database (HGMD) public        database, “HapMap”=SNP observed in the International HapMap        Project public database, “CSNP”=SNP observed in an internal        Applied Biosystems (Foster City, Calif.) database of coding SNPS        (cSNPs).

Note that multiple “Applera” source entries for a single SNP indicatethat the same SNP was covered by multiple overlapping amplificationproducts and the re-sequencing results (e.g., observed allele counts)from each of these amplification products is being provided.

-   -   Population/allele/allele count information in the format of        [population 1        (first_allele,count|second_allele,count)population2(first_allele,count|second_allele,count)        total (first_allele,total count|second_allele,total count)]. The        information in this field includes populations/ethnic groups in        which particular SNP alleles have been observed        (“cau”=Caucasian, “his”=Hispanic, “chn”=Chinese, and        “afr”=African-American, “jpn”=Japanese, “ind”=Indian,        “mex”=Mexican, “ain”=“American Indian, “cra”=Celera donor,        “no_pop”=no population information available), identified SNP        alleles, and observed allele counts (within each population        group and total allele counts), where available [“-” in the        allele field represents a deletion allele of an        insertion/deletion (“indel”) polymorphism (in which case the        corresponding insertion allele, which may be comprised of one or        more nucleotides, is indicated in the allele field on the        opposite side of the “|”); “-” in the count field indicates that        allele count information is not available]. For certain SNPs        from the public dbSNP database, population/ethnic information is        indicated as follows (this population information is publicly        available in dbSNP): “HISP1”=human individual DNA (anonymized        samples) from 23 individuals of self-described HISPANIC        heritage; “PAC 1”=human individual DNA (anonymized samples) from        24 individuals of self-described PACIFIC RIM heritage;        “CAUC1”=human individual DNA (anonymized samples) from 31        individuals of self-described CAUCASIAN heritage; “AFR1”=human        individual DNA (anonymized samples) from 24 individuals of        self-described AFRICAN/AFRICAN AMERICAN heritage; “P1”=human        individual DNA (anonymized samples) from 102 individuals of        self-described heritage; “PA130299515”; “SC_12_A”=SANGER 12 DNAs        of Asian origin from Corielle cell repositories, 6 of which are        male and 6 female; “SC_12_C”=SANGER 12 DNAs of Caucasian origin        from Corielle cell repositories from the CEPH/UTAH library, six        male and six female; “SC_12_AA”=SANGER 12 DNAs of        African-American origin from Corielle cell repositories 6 of        which are male and 6 female; “SC_95_C”=SANGER 95 DNAs of        Caucasian origin from Corielle cell repositories from the        CEPH/UTAH library; and “SC_12_CA”=Caucasians−12 DNAs from        Corielle cell repositories that are from the CEPH/UTAH library,        six male and six female.

Note that for SNPs of “Applera” SNP source, genes/regulatory regions of39 individuals (20 Caucasians and 19 African Americans) werere-sequenced and, since each SNP position is represented by twochromosomes in each individual (with the exception of SNPs on X and Ychromosomes in males, for which each SNP position is represented by asingle chromosome), up to 78 chromosomes were genotyped for each SNPposition. Thus, the sum of the African-American (“afr”) allele counts isup to 38, the sum of the Caucasian allele counts (“cau”) is up to 40,and the total sum of all allele counts is up to 78.

Note that semicolons separate population/allele/count informationcorresponding to each indicated SNP source; i.e., if four SNP sourcesare indicated, such as “Celera,” “dbSNP,” “HGBASE,” and “HGMD,” thenpopulation/allele/count information is provided in four groups which areseparated by semicolons and listed in the same order as the listing ofSNP sources, with each population/allele/count information groupcorresponding to the respective SNP source based on order; thus, in thisexample, the first population/allele/count information group wouldcorrespond to the first listed SNP source (Celera) and the thirdpopulation/allele/count information group separated by semicolons wouldcorrespond to the third listed SNP source (HGBASE); ifpopulation/allele/count information is not available for any particularSNP source, then a pair of semicolons is still inserted as aplace-holder in order to maintain correspondence between the list of SNPsources and the corresponding listing of population/allele/countinformation.

-   -   SNP type (e.g., location within gene/transcript and/or predicted        functional effect) [“MIS-SENSE MUTATION”=SNP causes a change in        the encoded amino acid (i.e., a non-synonymous coding SNP);        “SILENT MUTATION”=SNP does not cause a change in the encoded        amino acid (i.e., a synonymous coding SNP); “STOP CODON        MUTATION”=SNP is located in a stop codon; “NONSENSE        MUTATION”=SNP creates or destroys a stop codon; “UTR 5”=SNP is        located in a 5′ UTR of a transcript; “UTR 3”=SNP is located in a        3′ UTR of a transcript; “PUTATIVE UTR 5” =SNP is located in a        putative 5′ UTR; “PUTATIVE UTR 3”=SNP is located in a putative        3′ UTR; “DONOR SPLICE SITE”=SNP is located in a donor splice        site (5′ intron boundary); “ACCEPTOR SPLICE SITE”=SNP is located        in an acceptor splice site (3′ intron boundary); “CODING        REGION”=SNP is located in a protein-coding region of the        transcript; “EXON”=SNP is located in an exon; “INTRON”=SNP is        located in an intron; “hmCS”=SNP is located in a human-mouse        conserved segment; “TFBS”=SNP is located in a transcription        factor binding site; “UNKNOWN”=SNP type is not defined;        “INTERGENIC”=SNP is intergenic, i.e., outside of any gene        boundary].    -   Protein coding information (Table 1 only), where relevant, in        the format of [protein SEQ ID NO, amino acid position, (amino        acid-1, codon1) (amino acid-2, codon2)]. The information in this        field includes SEQ ID NO of the encoded protein sequence,        position of the amino acid residue within the protein identified        by the SEQ ID NO that is encoded by the codon containing the        SNP, amino acids (represented by one-letter amino acid codes)        that are encoded by the alternative SNP alleles (in the case of        stop codons, “X” is used for the one-letter amino acid code),        and alternative codons containing the alternative SNP        nucleotides which encode the amino acid residues (thus, for        example, for missense mutation-type SNPs, at least two different        amino acids and at least two different codons are generally        indicated; for silent mutation-type SNPs, one amino acid and at        least two different codons are generally indicated, etc.). In        instances where the SNP is located outside of a protein-coding        region (e.g., in a UTR region), “None” is indicated following        the protein SEQ ID NO.

Description of Table 3

Table 3 provides a list of LD SNPs that are related to and derived fromcertain interrogated SNPs. The interrogated SNPs, which are shown incolumn 1 (which indicates the hCV identification numbers of eachinterrogated SNP) and column 2 (which indicates the public rsidentification numbers of each interrogated SNP) of Table 3, arestatistically significantly associated with VT risk (particularly riskfor recurrent VT) and/or statin response for reducing VT risk, asdescribed and shown herein, particularly in Tables 4-9 and in theExamples sections below. The LD SNPs are provided as an example of SNPswhich can also serve as markers for disease association based on theirbeing in LD with an interrogated SNP. The criteria and process ofselecting such LD SNPs, including the calculation of the r² value andthe threshold r² value, are described in Example 7, below.

In Table 3, the column labeled “Interrogated SNP” presents each markeras identified by its unique hCV identification number. The columnlabeled “Interrogated rs” presents the publicly known rs identificationnumber for the corresponding hCV number. The column labeled “LD SNP”presents the hCV numbers of the LD SNPs that are derived from theircorresponding interrogated SNPs. The column labeled “LD SNP rs” presentsthe publicly known rs identification number for the corresponding hCVnumber. The column labeled “Power” presents the level of power where ther² threshold is set. For example, when power is set at 0.51, thethreshold r² value calculated therefrom is the minimum r² that an LD SNPmust have in reference to an interrogated SNP, in order for the LD SNPto be classified as a marker capable of being associated with a diseasephenotype at greater than 51% probability. The column labeled “Thresholdr²” presents the minimum value of r² that an LD SNP must meet inreference to an interrogated SNP in order to qualify as an LD SNP. Thecolumn labeled “r²” presents the actual r² value of the LD SNP inreference to the interrogated SNP to which it is related.

Description of Tables 4-9

Tables 4-9 provide the results of analyses for SNPs disclosed in Tables1 and 2 (SNPs can be cross-referenced between all the tables hereinbased on their hCV and/or rs identification numbers).

The analyses in Tables 4-6 are further described in Example 1 below.

The analysis in Table 7 is further described in Example 3 below.

The analysis in Table 8 is further described in Example 4 below.

The analysis in Table 9 is further described in Example 5 below.

The results shown in Tables 4-9 provide support for the association ofthese SNPs with VT risk, particularly risk for recurrent VT, and/orresponse to statin treatment for reducing the risk of VT.

In Tables 4-6, “statin_1” or “statin user” are equivalent designationsthat refer to individuals who were using statins, and “statin_0” or“statin nonuser” are equivalent designations that refer to individualswho were not using statins.

Throughout Tables 4-9, “P” or “P-value” indicates the p-value, “p(int)”indicates the p(interaction) value, “OR” refers to the odds ratio, “HR”refers to the hazard ratio, and “95% CI” refers to the 95% confidenceinterval for the odds ratio or hazard ratio.

In Tables 7-9, “P_DF2” indicates the two degrees of freedom Wald Testp-value.

In Tables 8-9, “HW(control)pExact” indicates the Hardy-Weinberg p-valuefor all controls in the study.

With respect to drug response (e.g., response to a statin), if the OR orHR of those treated with the drug (e.g., a statin) compared with thosetreated with a placebo within a particular genotype (or with aparticular allele) is less than one, this indicates that an individualwith this particular genotype or allele would benefit from the drug (anOR or HR equal to one would indicate that the drug has no effect). Incontrast, with respect to drug response, if the OR or HR is greater thanone for a particular allele, then this indicates that an individual withthe other alternative allele would benefit from the drug. As usedherein, the term “benefit” (with respect to a preventive or therapeuticdrug treatment) is defined as achieving a reduced risk for a diseasethat the drug is intended to treat or prevent (e.g., VT) byadministering the drug treatment, compared with the risk for the diseasein the absence of receiving the drug treatment (or receiving a placeboin lieu of the drug treatment) for the same genotype.

With respect to disease risk, an OR or HR that is greater than oneindicates that a given allele is a risk allele (which may also bereferred to as a susceptibility allele), whereas an OR or HR that isless than one indicates that a given allele is a non-risk allele (whichmay also be referred to as a protective allele). For a given riskallele, the other alternative allele at the SNP position (which can bederived from the information provided in Tables 1-2, for example) may beconsidered a non-risk allele. For a given non-risk allele, the otheralternative allele at the SNP position may be considered a risk allele.Thus, with respect to disease risk, if the OR or HR for a particularallele at a SNP position is greater than one, this indicates that anindividual with this particular allele has a higher risk for the diseasethan an individual who has the other allele at the SNP position. Incontrast, if the OR for a particular allele is less than one, thisindicates that an individual with this particular allele has a reducedrisk for the disease compared with an individual who has the otherallele at the SNP position.

DETAILED DESCRIPTION OF THE INVENTION

Exemplary embodiments of the present invention provide SNPs associatedwith risk for developing venous thrombosis (VT) (interchangeablyreferred to as venous thromboembolism (VTE)) and/or response to statintreatment, particularly statin treatment for reducing the risk of VT,and methods for their use. The present invention further providesnucleic acid molecules containing these SNPs, methods and reagents forthe detection of the SNPs disclosed herein, uses of these SNPs for thedevelopment of detection reagents, and assays or kits that utilize suchreagents. The statin response-associated SNPs disclosed herein areparticularly useful for predicting, screening for, and evaluatingresponse to statin treatment, particularly for prevention or treatmentof VT using statins, in humans. The SNPs disclosed herein are alsouseful for diagnosing, prognosing, screening for, and evaluatingpredisposition to VT in humans. Furthermore, such SNPs and their encodedproducts are useful targets for the development of therapeutic andpreventive agents.

Thus, exemplary embodiments of the present invention provide individualSNPs associated with risk for developing VT and/or response to statintreatment, particularly statin treatment for reducing the risk of VT, aswell as combinations of SNPs and haplotypes, polymorphic/varianttranscript sequences (SEQ ID NOS:1-84) and genomic sequences (SEQ IDNOS:338-500) containing SNPs, encoded amino acid sequences (SEQ IDNOS:85-168), and both transcript-based SNP context sequences (SEQ IDNOS:169-337) and genomic-based SNP context sequences (SEQ IDNOS:501-3098) (transcript sequences, protein sequences, andtranscript-based SNP context sequences are provided in Table 1 and theSequence Listing; genomic sequences and genomic-based SNP contextsequences are provided in Table 2 and the Sequence Listing), methods ofdetecting these polymorphisms in a test sample, methods of determiningan individual's risk for developing VT, methods of determining if anindividual is likely to respond to a particular treatment such asstatins (particularly for treating or preventing VT), methods ofscreening for compounds useful for treating VT, compounds identified bythese screening methods, methods of using the disclosed SNPs to select atreatment/preventive strategy or therapeutic agent, and methods oftreating or preventing VT.

Exemplary embodiments of the present invention further provide methodsfor selecting or formulating a treatment regimen (e.g., methods fordetermining whether or not to administer statin treatment to anindividual having VT, or who is at risk for developing VT in the future,or who has previously had VT, methods for selecting a particularstatin-based treatment regimen such as dosage and frequency ofadministration of statin, or a particular form/type of statin such as aparticular pharmaceutical formulation or statin compound, methods foradministering an alternative, non-statin-based treatment (such aswarfarin or other anticoagulants, e.g., direct thrombin inhibitors suchas dabigatran, or direct factor Xa inhibitors such as rivaroxaban orapixaban) to individuals who are predicted to be unlikely to respondpositively to statin treatment, etc.), and methods for determining thelikelihood of experiencing toxicity or other undesirable side effectsfrom statin treatment, etc. The present invention also provides methodsfor selecting individuals to whom a statin or other therapeutic will beadministered based on the individual's genotype, and methods forselecting individuals for a clinical trial of a statin or othertherapeutic agent based on the genotypes of the individuals (e.g.,selecting individuals to participate in the trial who are most likely torespond positively from the statin treatment and/or excludingindividuals from the trial who are unlikely to respond positively fromthe statin treatment based on their SNP genotype(s), or selectingindividuals who are unlikely to respond positively to statins based ontheir SNP genotype(s) to participate in a clinical trial of another typeof drug that may benefit them).

Exemplary embodiments of the present invention may include novel SNPsassociated with VT risk and/or response to statin treatment, as well asSNPs that were previously known in the art, but were not previouslyknown to be associated with VT risk and/or response to statin treatment.Accordingly, the present invention may provide novel compositions andmethods based on novel SNPs disclosed herein, and may also provide novelmethods of using known, but previously unassociated, SNPs in methodsrelating to, for example, methods relating to evaluating an individual'slikelihood of responding to statin treatment (particularly statintreatment, including preventive treatment, of VT, including recurrentVT), evaluating an individual's likelihood of having or developing VT,and predicting the likelihood of an individual experiencing a recurrenceof VT. In Tables 1 and 2, known SNPs are identified based on the publicdatabase in which they have been observed, which is indicated as one ormore of the following SNP types: “dbSNP”=SNP observed in dbSNP,“HGBASE”=SNP observed in HGBASE, and “HGMD”=SNP observed in the HumanGene Mutation Database (HGMD).

Particular alleles of the SNPs disclosed herein can be associated witheither an increased likelihood of responding to statin treatment(particularly for reducing the risk of VT) or increased risk ofdeveloping VT, or a decreased likelihood of responding to statintreatment or a decreased risk of developing VT. Thus, whereas certainSNPs (or their encoded products) can be assayed to determine whether anindividual possesses a SNP allele that is indicative of an increasedlikelihood of responding to statin treatment or an increased risk ofdeveloping VT, other SNPs (or their encoded products) can be assayed todetermine whether an individual possesses a SNP allele that isindicative of a decreased likelihood of responding to statin treatmentor a decreased risk of developing VT. Similarly, particular alleles ofthe SNPs disclosed herein can be associated with either an increased ordecreased likelihood of having a recurrence of VT, or of experiencingtoxic effects from a particular treatment or therapeutic compound suchas statins, etc. The term “altered” may be used herein to encompasseither of these two possibilities (e.g., either an increased or adecreased likelihood/risk). SNP alleles that are associated with adecreased risk of having or developing VT may be referred to as“protective” alleles, and SNP alleles that are associated with anincreased risk of having or developing VT may be referred to as“susceptibility” alleles, “risk” alleles, or “risk factors”.

Those skilled in the art will readily recognize that nucleic acidmolecules may be double-stranded molecules and that reference to aparticular site on one strand refers, as well, to the corresponding siteon a complementary strand. In defining a SNP position, SNP allele, ornucleotide sequence, reference to an adenine, a thymine (uridine), acytosine, or a guanine at a particular site on one strand of a nucleicacid molecule also defines the thymine (uridine), adenine, guanine, orcytosine (respectively) at the corresponding site on a complementarystrand of the nucleic acid molecule. Thus, reference may be made toeither strand in order to refer to a particular SNP position, SNPallele, or nucleotide sequence. Probes and primers, may be designed tohybridize to either strand and SNP genotyping methods disclosed hereinmay generally target either strand. Throughout the specification, inidentifying a SNP position, reference is generally made to theprotein-encoding strand, only for the purpose of convenience.

References to variant peptides, polypeptides, or proteins of the presentinvention include peptides, polypeptides, proteins, or fragmentsthereof, that contain at least one amino acid residue that differs fromthe corresponding amino acid sequence of the art-knownpeptide/polypeptide/protein (the art-known protein may beinterchangeably referred to as the “wild-type,” “reference,” or “normal”protein). Such variant peptides/polypeptides/proteins can result from acodon change caused by a nonsynonymous nucleotide substitution at aprotein-coding SNP position (i.e., a missense mutation) disclosed by thepresent invention. Variant peptides/polypeptides/proteins of the presentinvention can also result from a nonsense mutation (i.e., a SNP thatcreates a premature stop codon, a SNP that generates a read-throughmutation by abolishing a stop codon), or due to any SNP disclosed by thepresent invention that otherwise alters the structure, function,activity, or expression of a protein, such as a SNP in a regulatoryregion (e.g. a promoter or enhancer) or a SNP that leads to alternativeor defective splicing, such as a SNP in an intron or a SNP at anexon/intron boundary. As used herein, the terms “polypeptide,”“peptide,” and “protein” are used interchangeably.

As used herein, an “allele” may refer to a nucleotide at a SNP position(wherein at least two alternative nucleotides exist in the population atthe SNP position, in accordance with the inherent definition of a SNP)or may refer to an amino acid residue that is encoded by the codon whichcontains the SNP position (where the alternative nucleotides that arepresent in the population at the SNP position form alternative codonsthat encode different amino acid residues). An “allele” may also bereferred to herein as a “variant”. Also, an amino acid residue that isencoded by a codon containing a particular SNP may simply be referred toas being encoded by the SNP.

A phrase such as “represented by”, “as represented by”, “as shown by”,“as symbolized by”, or “as designated by” may be used herein to refer toa SNP within a sequence (e.g., a polynucleotide context sequencesurrounding a SNP), such as in the context of “a polymorphism asrepresented by position 101 of SEQ ID NO:X or its complement”.Typically, the sequence surrounding a SNP may be recited when referringto a SNP, however the sequence is not intended as a structurallimitation beyond the specific SNP position itself. Rather, the sequenceis recited merely as a way of referring to the SNP (in this example,“SEQ ID NO:X or its complement” is recited in order to refer to the SNPlocated at position 101 of SEQ ID NO:X, but SEQ ID NO:X or itscomplement is not intended as a structural limitation beyond thespecific SNP position itself). In other words, it is recognized that thecontext sequence of SEQ ID NO:X in this example may contain one or morepolymorphic nucleotide positions outside of position 101 and thereforean exact match over the full-length of SEQ ID NO:X is irrelevant sinceSEQ ID NO:X is only meant to provide context for referring to the SNP atposition 101 of SEQ ID NO:X. Likewise, the length of the contextsequence is also irrelevant (100 nucleotides on each side of a SNPposition has been arbitrarily used in the present application as thelength for context sequences merely for convenience and because 201nucleotides of total length is expected to provide sufficient uniquenessto unambiguously identify a given nucleotide sequence). Thus, since aSNP is a variation at a single nucleotide position, it is customary torefer to context sequence (e.g., SEQ ID NO:X in this example)surrounding a particular SNP position in order to uniquely identify andrefer to the SNP. Alternatively, a SNP can be referred to by a uniqueidentification number such as a public “rs” identification number or aninternal “hCV” identification number, such as provided herein for eachSNP (e.g., in Tables 1-2). For example, in the instant application,“rs2036914”, “hCV12066124”, and “position 101 of SEQ ID NO:713” allrefer to the same SNP.

As used herein, the term “benefit” (with respect to a preventive ortherapeutic drug treatment, such as statin treatment) is defined asachieving a reduced risk for a disease that the drug is intended totreat or prevent (e.g., VT) by administrating the drug treatment,compared with the risk for the disease in the absence of receiving thedrug treatment (or receiving a placebo in lieu of the drug treatment)for the same genotype. The term “benefit” may be used hereininterchangeably with terms such as “respond positively” or “positivelyrespond”.

As used herein, the terms “drug” and “therapeutic agent” are usedinterchangeably, and may include, but are not limited to, small moleculecompounds, biologics (e.g., antibodies, proteins, protein fragments,fusion proteins, glycoproteins, etc.), nucleic acid agents (e.g.,antisense, RNAi/siRNA, and microRNA molecules, etc.), vaccines, etc.,which may be used for therapeutic and/or preventive treatment of adisease (e.g., VT).

Examples of statins (also known as HMG-CoA reductase inhibitors)include, but are not limited to, atorvastatin (Lipitor®), rosuvastatin(Crestor®), pravastatin (Pravachol®), simvastatin (Zocor®), fluvastatin(Lescol®), and lovastatin (Mevacor®), as well as combination therapiesthat include a statin such as simvastatin+ezetimibe (Vytorin®),lovastatin+niacin (Advicor®), atorvastatin+amlodipine besylate(Caduet®), and simvastatin+niacin (Simcor®).

Certain exemplary embodiments of the invention provide the followingcompositions and uses: (1) a reagent (such as an allele-specific probeor primer, or any other oligonucleotide or other reagent suitable fordetecting a polymorphism disclosed herein, which can include detectionof any allele of the polymorphism) for use as a diagnostic or predictiveagent for determining VT risk and/or statin response, particularly forreducing the risk of VT; (2) a kit, device, array, or assay componentthat includes or is coupled with the reagent of (1) above for use indetermining VT risk and/or statin response, particularly for reducingthe risk of VT; (3) the use of the reagent of (1) above for themanufacture of a kit, device, array, or assay component for determiningVT risk and/or statin response, particularly for reducing the risk ofVT; and (4) the use of a polymorphism disclosed herein for themanufacture of a reagent for use as a diagnostic or predictive agent fordetermining VT risk and/or statin response, particularly for reducingthe risk of VT.

The various methods described herein, such as correlating the presenceor absence of a polymorphism with the predicted response of anindividual to a drug such as a statin, particularly for reducing therisk for VT, and/or correlating the presence or absence of apolymorphism with an altered (e.g., increased or decreased) risk (or noaltered risk) for developing VT, can be carried out by automated methodssuch as by using a computer (or other apparatus/devices such asbiomedical devices, laboratory instrumentation, or otherapparatus/devices having a computer processor) programmed to carry outany of the methods described herein. For example, computer software(which may be interchangeably referred to herein as a computer program)can perform the step of correlating the presence or absence of apolymorphism in an individual with an altered (e.g., increased ordecreased) response (or no altered response) to statin treatment forreducing the risk for VT, and/or correlating the presence or absence ofa polymorphism with an altered (e.g., increased or decreased) risk (orno altered risk) for developing VT. Accordingly, certain embodiments ofthe invention provide a computer (or other apparatus/device) programmedto carry out any of the methods described herein.

Reagants, and kits containing the reagents, for detecting a SNPdisclosed herein can be manufactured in compliance with regulatoryrequirements for clinical diagnostic use, such as those set forth by theUnited States Food and Drug Administration (FDA). Reagents and kits canbe manufactured in compliance with “good manufacturing practice” (GMP)guidelines, such as “current good manufacturing practices” (cGMP)guidelines in the United States. Furthermore, reagents and kits can beregistered with the FDA (such as by satisfying 510(k) Pre-MarketNotification (PMN) requirements or obtaining Pre-Market Approval (PMA)).Reagents (particularly reagents for clinical diagnostic use) fordetecting a SNP disclosed herein can be classified by the FDA (or otheragency) as an analyte specific reagent (ASR) (or similarclassification), and kits (particularly kits for clinical diagnosticuse) containing reagents for detecting a SNP disclosed herein can beclassified by the FDA (or other agency) as in vitro diagnostic (IVD)kits or laboratory developed tests (LDTs) (or similar classifications),including in vitro diagnostic multivariate index assays (IVDMIAs).Furthermore, reagents and kits can be classified by the FDA (or otheragency) as Class I, Class II, or Class III medical devices. Reagents andkits can also be registered with (e.g., approved by) and/or manufacturedin compliance with regulatory requirements set forth by the ClinicalLaboratory Improvement Amendments Act (CLIA), which is administered bythe Centers for Medicare and Medicaid Services (CMS), or other agenciesin the United States or throughout the rest of the world.

Reports, Programmed Computers, Business Methods, and Systems

The results of a test (e.g., an individual's predicted responsiveness tostatin treatment, or an individual's risk for developing VT, based onassaying one or more SNPs disclosed herein, and/or an individual'sallele(s)/genotype at one or more SNPs disclosed herein, etc.), and/orany other information pertaining to a test, may be referred to herein asa “report”. A tangible report can optionally be generated as part of atesting process (which may be interchangeably referred to herein as“reporting”, or as “providing” a report, “producing” a report, or“generating” a report).

Examples of tangible reports may include, but are not limited to,reports in paper (such as computer-generated printouts of test results)or equivalent formats and reports stored on computer readable medium(such as a CD, USB flash drive or other removable storage device,computer hard drive, or computer network server, etc.). Reports,particularly those stored on computer readable medium, can be part of adatabase, which may optionally be accessible via the internet (such as adatabase of patient records or genetic information stored on a computernetwork server, which may be a “secure database” that has securityfeatures that limit access to the report, such as to allow only thepatient and the patient's medical practioners to view the report whilepreventing other unauthorized individuals from viewing the report, forexample). In addition to, or as an alternative to, generating a tangiblereport, reports can also be displayed on a computer screen (or thedisplay of another electronic device or instrument).

A report can include, for example, an individual's predicted risk fordeveloping DVT and/or predicted responsiveness to statin treatment(e.g., whether the individual will benefit from statin treatment byhaving their risk for VT reduced), or may just include theallele(s)/genotype that an individual carries at one or more SNPsdisclosed herein, which may optionally be linked to informationregarding the significance of having the allele(s)/genotype at the SNP(for example, a report on computer readable medium such as a networkserver may include hyperlink(s) to one or more journal publications orwebsites that describe the medical/biological implications, such asstatin response and/or VT risk, for individuals having a certainallele/genotype at the SNP). Thus, for example, the report can includedrug responsiveness, disease risk, and/or other medical/biologicalsignificance, as well as optionally also including the allele/genotypeinformation, or the report may just include allele/genotype informationwithout including drug responsiveness, disease risk, or othermedical/biological significance (such that an individual viewing thereport can use the allele/genotype information to determine theassociated drug response, disease risk, or other medical/biologicalsignificance from a source outside of the report itself, such as from amedical practioner, publication, website, etc., which may optionally belinked to the report such as by a hyperlink).

A report can further be “transmitted” or “communicated” (these terms maybe used herein interchangeably), such as to the individual who wastested, a medical practitioner (e.g., a doctor, nurse, clinicallaboratory practitioner, genetic counselor, etc.), a healthcareorganization, a clinical laboratory, and/or any other party or requesterintended to view or possess the report. The act of “transmitting” or“communicating” a report can be by any means known in the art, based onthe format of the report. Furthermore, “transmitting” or “communicating”a report can include delivering/sending a report (“pushing”) and/orretrieving (“pulling”) a report. For example, reports can betransmitted/communicated by various means, including being physicallytransferred between parties (such as for reports in paper format) suchas by being physically delivered from one party to another, or by beingtransmitted electronically (e.g., via e-mail or over the internet, byfacsimile, and/or by any wired or wireless communication methods knownin the art) such as by being retrieved from a database stored on acomputer network server, etc.

In certain exemplary embodiments, the invention provides computers (orother apparatus/devices such as biomedical devices or laboratoryinstrumentation) programmed to carry out the methods described herein.For example, in certain embodiments, the invention provides a computerprogrammed to receive (i.e., as input) the identity (e.g., the allele(s)or genotype at a SNP) of one or more SNPs disclosed herein and provide(i.e., as output) the disease risk (e.g., an individual's predictedstatin responsiveness or risk for developing VT) or other result basedon the identity of the SNP(s). Such output (e.g., communication ofdisease risk, disease diagnosis or prognosis, drug responsiveness, etc.)may be, for example, in the form of a report on computer readablemedium, printed in paper form, and/or displayed on a computer screen orother display.

In various exemplary embodiments, the invention further provides methodsof doing business (with respect to methods of doing business, the terms“individual” and “customer” are used herein interchangeably). Forexample, exemplary methods of doing business can comprise assaying oneor more SNPs disclosed herein and providing a report that includes, forexample, a customer's predicted response to statin treatment (e.g., forreducing their risk for VT) or their risk for developing VT (based onwhich allele(s)/genotype is present at the assayed SNP(s)) and/or thatincludes the allele(s)/genotype at the assayed SNP(s) which mayoptionally be linked to information (e.g., journal publications,websites, etc.) pertaining to disease risk or other biological/medicalsignificance such as by means of a hyperlink (the report may beprovided, for example, on a computer network server or other computerreadable medium that is internet-accessible, and the report may beincluded in a secure database that allows the customer to access theirreport while preventing other unauthorized individuals from viewing thereport), and optionally transmitting the report. Customers (or anotherparty who is associated with the customer, such as the customer'sdoctor, for example) can request/order (e.g., purchase) the test onlinevia the internet (or by phone, mail order, at an outlet/store, etc.),for example, and a kit can be sent/delivered (or otherwise provided) tothe customer (or another party on behalf of the customer, such as thecustomer's doctor, for example) for collection of a biological samplefrom the customer (e.g., a buccal swab for collecting buccal cells), andthe customer (or a party who collects the customer's biological sample)can submit their biological samples for assaying (e.g., to a laboratoryor party associated with the laboratory such as a party that accepts thecustomer samples on behalf of the laboratory, a party for whom thelaboratory is under the control of (e.g., the laboratory carries out theassays by request of the party or under a contract with the party, forexample), and/or a party that receives at least a portion of thecustomer's payment for the test). The report (e.g., results of the assayincluding, for example, the customer's disease risk and/orallele(s)/genotype at the assayed SNP(s)) may be provided to thecustomer by, for example, the laboratory that assays the SNP(s) or aparty associated with the laboratory (e.g., a party that receives atleast a portion of the customer's payment for the assay, or a party thatrequests the laboratory to carry out the assays or that contracts withthe laboratory for the assays to be carried out) or a doctor or othermedical practitioner who is associated with (e.g., employed by or havinga consulting or contracting arrangement with) the laboratory or with aparty associated with the laboratory, or the report may be provided to athird party (e.g., a doctor, genetic counselor, hospital, etc.) whichoptionally provides the report to the customer. In further embodiments,the customer may be a doctor or other medical practitioner, or ahospital, laboratory, medical insurance organization, or other medicalorganization that requests/orders (e.g., purchases) tests for thepurposes of having other individuals (e.g., their patients or customers)assayed for one or more SNPs disclosed herein and optionally obtaining areport of the assay results.

In certain exemplary methods of doing business, a kit for collecting abiological sample (e.g., a buccal swab for collecting buccal cells, orother sample collection device) is provided to a medical practitioner(e.g., a physician) which the medical practitioner uses to obtain asample (e.g., buccal cells, saliva, blood, etc.) from a patient, thesample is then sent to a laboratory (e.g., a CLIA-certified laboratory)or other facility that tests the sample for one or more SNPs disclosedherein (e.g., to determine the genotype of one or more SNPs disclosedherein, such as to determine the patient's predicted response to statintreatment for reducing their risk for VT, and/or their risk fordeveloping VT), and the results of the test (e.g., the patient'sgenotype at one or more SNPs disclosed herein and/or the patient'spredicted statin response or VT risk based on their SNP genotype) areprovided back to the medical practitioner (and/or directly to thepatient and/or to another party such as a hospital, medical insurancecompany, genetic counselor, etc.) who may then provide or otherwiseconvey the results to the patient. The results are typically provided inthe form of a report, such as described above.

In certain further exemplary methods of doing business, kits forcollecting a biological sample from a customer (e.g., a buccal swab forcollecting buccal cells, or other sample collection device) are provided(e.g., for sale), such as at an outlet (e.g., a drug store, pharmacy,general merchandise store, or any other desirable outlet), online viathe internet, by mail order, etc., whereby customers can obtain (e.g.,purchase) the kits, collect their own biological samples, and submit(e.g., send/deliver via mail) their samples to a laboratory (e.g., aCLIA-certified laboratory) or other facility which tests the samples forone or more SNPs disclosed herein (e.g., to determine the genotype ofone or more SNPs disclosed herein, such as to determine the customer'spredicted response to statin treatment for reducing their risk for VT,and/or their risk for developing VT) and provides the results of thetest (e.g., of the customer's genotype at one or more SNPs disclosedherein and/or the customer's statin response or VT risk based on theirSNP genotype) back to the customer and/or to a third party (e.g., aphysician or other medical practitioner, hospital, medical insurancecompany, genetic counselor, etc.). The results are typically provided inthe form of a report, such as described above. If the results of thetest are provided to a third party, then this third party may optionallyprovide another report to the customer based on the results of the test(e.g., the result of the test from the laboratory may provide thecustomer's genotype at one or more SNPs disclosed herein without statinresponse or VT risk information, and the third party may provide areport of the customer's statin response or VT risk based on thisgenotype result).

Certain further embodiments of the invention provide a system fordetermining whether an individual will benefit from statin treatment (orother therapy) in reducing VT risk, or for determining an individual'srisk for developing VT. Certain exemplary systems comprise an integrated“loop” in which an individual (or their medical practitioner) requests adetermination of such individual's predicted statin response (or VTrisk, etc.), this determination is carried out by testing a sample fromthe individual, and then the results of this determination are providedback to the requestor. For example, in certain systems, a sample (e.g.,buccal cells, saliva, blood, etc.) is obtained from an individual fortesting (the sample may be obtained by the individual or, for example,by a medical practitioner), the sample is submitted to a laboratory (orother facility) for testing (e.g., determining the genotype of one ormore SNPs disclosed herein), and then the results of the testing aresent to the patient (which optionally can be done by first sending theresults to an intermediary, such as a medical practioner, who thenprovides or otherwise conveys the results to the individual and/or actson the results), thereby forming an integrated loop system fordetermining an individual's predicted statin response (or VT risk,etc.). The portions of the system in which the results are transmitted(e.g., between any of a testing facility, a medical practitioner, and/orthe individual) can be carried out by way of electronic transmission(e.g., by computer such as via e-mail or the internet, by providing theresults on a website or computer network server which may optionally bea secure database, by phone or fax, or by any other wired or wirelesstransmission methods known in the art). Optionally, the system canfurther include a risk reduction component (i.e., a disease managementsystem) as part of the integrated loop (for an example of a diseasemanagement system, see U.S. Pat. No. 6,770,029, “Disease managementsystem and method including correlation assessment”). For example, theresults of the test can be used to reduce the risk of the disease in theindividual who was tested, such as by implementing a preventive therapyregimen (e.g., administration of a statin or other drug for reducing VTrisk), modifying the individual's diet, increasing exercise, reducingstress, and/or implementing any other physiological or behavioralmodifications in the individual with the goal of reducing disease risk.For reducing VT risk, this may include any means used in the art forimproving aspects of an individual's health relevant to reducing VTrisk. Thus, in exemplary embodiments, the system is controlled by theindividual and/or their medical practioner in that the individual and/ortheir medical practioner requests the test, receives the test resultsback, and (optionally) acts on the test results to reduce theindividual's disease risk, such as by implementing a disease managementsystem.

Isolated Nucleic Acid Molecules and SNP Detection Reagents & Kits

Tables 1 and 2 provide a variety of information about each SNP of thepresent invention that is associated with risk for developing VT and/orresponse to statin treatment (particularly for reducing an individual'srisk for VT), including the transcript sequences (SEQ ID NOS:1-84),genomic sequences (SEQ ID NOS:338-500), and protein sequences (SEQ IDNOS:85-168) of the encoded gene products (with the SNPs indicated by IUBcodes in the nucleic acid sequences). In addition, Tables 1 and 2include SNP context sequences, which generally include 100 nucleotideupstream (5′) plus 100 nucleotides downstream (3′) of each SNP position(SEQ ID NOS:169-337 correspond to transcript-based SNP context sequencesdisclosed in Table 1, and SEQ ID NOS:501-3098 correspond togenomic-based context sequences disclosed in Table 2), the alternativenucleotides (alleles) at each SNP position, and additional informationabout the variant where relevant, such as SNP type (coding, missense,splice site, UTR, etc.), human populations in which the SNP wasobserved, observed allele frequencies, information about the encodedprotein, etc.

Isolated Nucleic Acid Molecules

Exemplary embodiments of the invention provide isolated nucleic acidmolecules that contain one or more SNPs disclosed herein, particularlySNPs disclosed in Table 1 and/or Table 2. Isolated nucleic acidmolecules containing one or more SNPs disclosed herein (such as in atleast one of Tables 1 and 2) may be interchangeably referred tothroughout the present text as “SNP-containing nucleic acid molecules.”Isolated nucleic acid molecules may optionally encode a full-lengthvariant protein or fragment thereof. The isolated nucleic acid moleculesof the present invention also include probes and primers (which aredescribed in greater detail below in the section entitled “SNP DetectionReagents”), which may be used for assaying the disclosed SNPs, andisolated full-length genes, transcripts, cDNA molecules, and fragmentsthereof, which may be used for such purposes as expressing an encodedprotein.

As used herein, an “isolated nucleic acid molecule” generally is onethat contains a SNP of the present invention or one that hybridizes tosuch molecule such as a nucleic acid with a complementary sequence, andis separated from most other nucleic acids present in the natural sourceof the nucleic acid molecule. Moreover, an “isolated” nucleic acidmolecule, such as a cDNA molecule containing a SNP of the presentinvention, can be substantially free of other cellular material, orculture medium when produced by recombinant techniques, or chemicalprecursors or other chemicals when chemically synthesized. A nucleicacid molecule can be fused to other coding or regulatory sequences andstill be considered “isolated.” Nucleic acid molecules present innon-human transgenic animals, which do not naturally occur in theanimal, are also considered “isolated.” For example, recombinant DNAmolecules contained in a vector are considered “isolated.” Furtherexamples of “isolated” DNA molecules include recombinant DNA moleculesmaintained in heterologous host cells, and purified (partially orsubstantially) DNA molecules in solution. Isolated RNA molecules includein vivo or in vitro RNA transcripts of the isolated SNP-containing DNAmolecules of the present invention. Isolated nucleic acid moleculesaccording to the present invention further include such moleculesproduced synthetically.

Generally, an isolated SNP-containing nucleic acid molecule comprisesone or more SNP positions disclosed by the present invention withflanking nucleotide sequences on either side of the SNP positions. Aflanking sequence can include nucleotide residues that are naturallyassociated with the SNP site and/or heterologous nucleotide sequences.Preferably, the flanking sequence is up to about 500, 300, 100, 60, 50,30, 25, 20, 15, 10, 8, or 4 nucleotides (or any other length in-between)on either side of a SNP position, or as long as the full-length gene orentire protein-coding sequence (or any portion thereof such as an exon),especially if the SNP-containing nucleic acid molecule is to be used toproduce a protein or protein fragment.

For full-length genes and entire protein-coding sequences, a SNPflanking sequence can be, for example, up to about 5 KB, 4 KB, 3 KB, 2KB, 1 KB on either side of the SNP. Furthermore, in such instances theisolated nucleic acid molecule comprises exonic sequences (includingprotein-coding and/or non-coding exonic sequences), but may also includeintronic sequences. Thus, any protein coding sequence may be eithercontiguous or separated by introns. The important point is that thenucleic acid is isolated from remote and unimportant flanking sequencesand is of appropriate length such that it can be subjected to thespecific manipulations or uses described herein such as recombinantprotein expression, preparation of probes and primers for assaying theSNP position, and other uses specific to the SNP-containing nucleic acidsequences.

An isolated SNP-containing nucleic acid molecule can comprise, forexample, a full-length gene or transcript, such as a gene isolated fromgenomic DNA (e.g., by cloning or PCR amplification), a cDNA molecule, oran mRNA transcript molecule. Polymorphic transcript sequences arereferred to in Table 1 and provided in the Sequence Listing (SEQ IDNOS:1-84), and polymorphic genomic sequences are referred to in Table 2and provided in the Sequence Listing (SEQ ID NOS:338-500). Furthermore,fragments of such full-length genes and transcripts that contain one ormore SNPs disclosed herein are also encompassed by the presentinvention, and such fragments may be used, for example, to express anypart of a protein, such as a particular functional domain or anantigenic epitope.

Thus, the present invention also encompasses fragments of the nucleicacid sequences as disclosed in Tables 1 and 2 (transcript sequences arereferred to in Table 1 as SEQ ID NOS:1-84, genomic sequences arereferred to in Table 2 as SEQ ID NOS:338-500, transcript-based SNPcontext sequences are referred to in Table 1 as SEQ ID NOS:169-337, andgenomic-based SNP context sequences are referred to in Table 2 as SEQ IDNOS:501-3098) and their complements. The actual sequences referred to inthe tables are provided in the Sequence Listing. A fragment typicallycomprises a contiguous nucleotide sequence at least about 8 or morenucleotides, more preferably at least about 12 or more nucleotides, andeven more preferably at least about 16 or more nucleotides. Furthermore,a fragment could comprise at least about 18, 20, 22, 25, 30, 40, 50, 60,80, 100, 150, 200, 250 or 500 nucleotides in length (or any other numberin between). The length of the fragment will be based on its intendeduse. For example, the fragment can encode epitope-bearing regions of avariant peptide or regions of a variant peptide that differ from thenormal/wild-type protein, or can be useful as a polynucleotide probe orprimer. Such fragments can be isolated using the nucleotide sequencesprovided in Table 1 and/or Table 2 for the synthesis of a polynucleotideprobe. A labeled probe can then be used, for example, to screen a cDNAlibrary, genomic DNA library, or mRNA to isolate nucleic acidcorresponding to the coding region. Further, primers can be used inamplification reactions, such as for purposes of assaying one or moreSNPs sites or for cloning specific regions of a gene.

An isolated nucleic acid molecule of the present invention furtherencompasses a SNP-containing polynucleotide that is the product of anyone of a variety of nucleic acid amplification methods, which are usedto increase the copy numbers of a polynucleotide of interest in anucleic acid sample. Such amplification methods are well known in theart, and they include but are not limited to, polymerase chain reaction(PCR) (U.S. Pat. Nos. 4,683,195 and 4,683,202; PCR Technology:Principles and Applications for DNA Amplification, ed. H. A. Erlich,Freeman Press, NY, N.Y. (1992)), ligase chain reaction (LCR) (Wu andWallace, Genomics 4:560 (1989); Landegren et al., Science 241:1077(1988)), strand displacement amplification (SDA) (U.S. Pat. Nos.5,270,184 and 5,422,252), transcription-mediated amplification (TMA)(U.S. Pat. No. 5,399,491), linked linear amplification (LLA) (U.S. Pat.No. 6,027,923) and the like, and isothermal amplification methods suchas nucleic acid sequence based amplification (NASBA) and self-sustainedsequence replication (Guatelli et al., Proc Natl Acad Sci USA 87:1874(1990)). Based on such methodologies, a person skilled in the art canreadily design primers in any suitable regions 5′ and 3′ to a SNPdisclosed herein. Such primers may be used to amplify DNA of any lengthso long that it contains the SNP of interest in its sequence.

As used herein, an “amplified polynucleotide” of the invention is aSNP-containing nucleic acid molecule whose amount has been increased atleast two fold by any nucleic acid amplification method performed invitro as compared to its starting amount in a test sample. In otherpreferred embodiments, an amplified polynucleotide is the result of atleast ten fold, fifty fold, one hundred fold, one thousand fold, or eventen thousand fold increase as compared to its starting amount in a testsample. In a typical PCR amplification, a polynucleotide of interest isoften amplified at least fifty thousand fold in amount over theunamplified genomic DNA, but the precise amount of amplification neededfor an assay depends on the sensitivity of the subsequent detectionmethod used.

Generally, an amplified polynucleotide is at least about 16 nucleotidesin length. More typically, an amplified polynucleotide is at least about20 nucleotides in length. In a preferred embodiment of the invention, anamplified polynucleotide is at least about 30 nucleotides in length. Ina more preferred embodiment of the invention, an amplifiedpolynucleotide is at least about 32, 40, 45, 50, or 60 nucleotides inlength. In yet another preferred embodiment of the invention, anamplified polynucleotide is at least about 100, 200, 300, 400, or 500nucleotides in length. While the total length of an amplifiedpolynucleotide of the invention can be as long as an exon, an intron orthe entire gene where the SNP of interest resides, an amplified productis typically up to about 1,000 nucleotides in length (although certainamplification methods may generate amplified products greater than 1000nucleotides in length). More preferably, an amplified polynucleotide isnot greater than about 600-700 nucleotides in length. It is understoodthat irrespective of the length of an amplified polynucleotide, a SNP ofinterest may be located anywhere along its sequence.

In a specific embodiment of the invention, the amplified product is atleast about 201 nucleotides in length, comprises one of thetranscript-based context sequences or the genomic-based contextsequences shown in Tables 1 and 2. Such a product may have additionalsequences on its 5′ end or 3′ end or both. In another embodiment, theamplified product is about 101 nucleotides in length, and it contains aSNP disclosed herein. Preferably, the SNP is located at the middle ofthe amplified product (e.g., at position 101 in an amplified productthat is 201 nucleotides in length, or at position 51 in an amplifiedproduct that is 101 nucleotides in length), or within 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 12, 15, or 20 nucleotides from the middle of the amplifiedproduct. However, as indicated above, the SNP of interest may be locatedanywhere along the length of the amplified product.

The present invention provides isolated nucleic acid molecules thatcomprise, consist of, or consist essentially of one or morepolynucleotide sequences that contain one or more SNPs disclosed herein,complements thereof, and SNP-containing fragments thereof.

Accordingly, the present invention provides nucleic acid molecules thatconsist of any of the nucleotide sequences shown in Table 1 and/or Table2 (transcript sequences are referred to in Table 1 as SEQ ID NOS:1-84,genomic sequences are referred to in Table 2 as SEQ ID NOS:338-500,transcript-based SNP context sequences are referred to in Table 1 as SEQID NOS:169-337, and genomic-based SNP context sequences are referred toin Table 2 as SEQ ID NOS:501-3098), or any nucleic acid molecule thatencodes any of the variant proteins referred to in Table 1 (SEQ IDNOS:85-168). The actual sequences referred to in the tables are providedin the Sequence Listing. A nucleic acid molecule consists of anucleotide sequence when the nucleotide sequence is the completenucleotide sequence of the nucleic acid molecule.

The present invention further provides nucleic acid molecules thatconsist essentially of any of the nucleotide sequences referred to inTable 1 and/or Table 2 (transcript sequences are referred to in Table 1as SEQ ID NOS:1-84, genomic sequences are referred to in Table 2 as SEQID NOS:338-500, transcript-based SNP context sequences are referred toin Table 1 as SEQ ID NOS:169-337, and genomic-based SNP contextsequences are referred to in Table 2 as SEQ ID NOS:501-3098), or anynucleic acid molecule that encodes any of the variant proteins referredto in Table 1 (SEQ ID NOS:85-168). The actual sequences referred to inthe tables are provided in the Sequence Listing. A nucleic acid moleculeconsists essentially of a nucleotide sequence when such a nucleotidesequence is present with only a few additional nucleotide residues inthe final nucleic acid molecule.

The present invention further provides nucleic acid molecules thatcomprise any of the nucleotide sequences shown in Table 1 and/or Table 2or a SNP-containing fragment thereof (transcript sequences are referredto in Table 1 as SEQ ID NOS:1-84, genomic sequences are referred to inTable 2 as SEQ ID NOS:338-500, transcript-based SNP context sequencesare referred to in Table 1 as SEQ ID NOS:169-337, and genomic-based SNPcontext sequences are referred to in Table 2 as SEQ ID NOS:501-3098), orany nucleic acid molecule that encodes any of the variant proteinsprovided in Table 1 (SEQ ID NOS:85-168). The actual sequences referredto in the tables are provided in the Sequence Listing. A nucleic acidmolecule comprises a nucleotide sequence when the nucleotide sequence isat least part of the final nucleotide sequence of the nucleic acidmolecule. In such a fashion, the nucleic acid molecule can be only thenucleotide sequence or have additional nucleotide residues, such asresidues that are naturally associated with it or heterologousnucleotide sequences. Such a nucleic acid molecule can have one to a fewadditional nucleotides or can comprise many more additional nucleotides.A brief description of how various types of these nucleic acid moleculescan be readily made and isolated is provided below, and such techniquesare well known to those of ordinary skill in the art. Sambrook andRussell, Molecular Cloning: A Laboratory Manual, Cold Spring HarborPress, N.Y. (2000).

The isolated nucleic acid molecules can encode mature proteins plusadditional amino or carboxyl-terminal amino acids or both, or aminoacids interior to the mature peptide (when the mature form has more thanone peptide chain, for instance). Such sequences may play a role inprocessing of a protein from precursor to a mature form, facilitateprotein trafficking, prolong or shorten protein half-life, or facilitatemanipulation of a protein for assay or production. As generally is thecase in situ, the additional amino acids may be processed away from themature protein by cellular enzymes.

Thus, the isolated nucleic acid molecules include, but are not limitedto, nucleic acid molecules having a sequence encoding a peptide alone, asequence encoding a mature peptide and additional coding sequences suchas a leader or secretory sequence (e.g., a pre-pro or pro-proteinsequence), a sequence encoding a mature peptide with or withoutadditional coding sequences, plus additional non-coding sequences, forexample introns and non-coding 5′ and 3′ sequences such as transcribedbut untranslated sequences that play a role in, for example,transcription, mRNA processing (including splicing and polyadenylationsignals), ribosome binding, and/or stability of mRNA. In addition, thenucleic acid molecules may be fused to heterologous marker sequencesencoding, for example, a peptide that facilitates purification.

Isolated nucleic acid molecules can be in the form of RNA, such as mRNA,or in the form DNA, including cDNA and genomic DNA, which may beobtained, for example, by molecular cloning or produced by chemicalsynthetic techniques or by a combination thereof. Sambrook and Russell,Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, N.Y.(2000). Furthermore, isolated nucleic acid molecules, particularly SNPdetection reagents such as probes and primers, can also be partially orcompletely in the form of one or more types of nucleic acid analogs,such as peptide nucleic acid (PNA). U.S. Pat. Nos. 5,539,082; 5,527,675;5,623,049; and 5,714,331. The nucleic acid, especially DNA, can bedouble-stranded or single-stranded. Single-stranded nucleic acid can bethe coding strand (sense strand) or the complementary non-coding strand(anti-sense strand). DNA, RNA, or PNA segments can be assembled, forexample, from fragments of the human genome (in the case of DNA or RNA)or single nucleotides, short oligonucleotide linkers, or from a seriesof oligonucleotides, to provide a synthetic nucleic acid molecule.Nucleic acid molecules can be readily synthesized using the sequencesprovided herein as a reference; oligonucleotide and PNA oligomersynthesis techniques are well known in the art. See, e.g., Corey,“Peptide nucleic acids: expanding the scope of nucleic acidrecognition,” Trends Biotechnol 15(6):224-9 (June 1997), and Hyrup etal., “Peptide nucleic acids (PNA): synthesis, properties and potentialapplications,” Bioorg Med Chem 4(1):5-23) (January 1996). Furthermore,large-scale automated oligonucleotide/PNA synthesis (including synthesison an array or bead surface or other solid support) can readily beaccomplished using commercially available nucleic acid synthesizers,such as the Applied Biosystems (Foster City, Calif.) 3900High-Throughput DNA Synthesizer or Expedite 8909 Nucleic Acid SynthesisSystem, and the sequence information provided herein.

The present invention encompasses nucleic acid analogs that containmodified, synthetic, or non-naturally occurring nucleotides orstructural elements or other alternative/modified nucleic acidchemistries known in the art. Such nucleic acid analogs are useful, forexample, as detection reagents (e.g., primers/probes) for detecting oneor more SNPs identified in Table 1 and/or Table 2. Furthermore,kits/systems (such as beads, arrays, etc.) that include these analogsare also encompassed by the present invention. For example, PNAoligomers that are based on the polymorphic sequences of the presentinvention are specifically contemplated. PNA oligomers are analogs ofDNA in which the phosphate backbone is replaced with a peptide-likebackbone. Lagriffoul et al., Bioorganic & Medicinal Chemistry Letters4:1081-1082 (1994); Petersen et al., Bioorganic & Medicinal ChemistryLetters 6:793-796 (1996); Kumar et al., Organic Letters 3(9):1269-1272(2001); WO 96/04000. PNA hybridizes to complementary RNA or DNA withhigher affinity and specificity than conventional oligonucleotides andoligonucleotide analogs. The properties of PNA enable novel molecularbiology and biochemistry applications unachievable with traditionaloligonucleotides and peptides.

Additional examples of nucleic acid modifications that improve thebinding properties and/or stability of a nucleic acid include the use ofbase analogs such as inosine, intercalators (U.S. Pat. No. 4,835,263)and the minor groove binders (U.S. Pat. No. 5,801,115). Thus, referencesherein to nucleic acid molecules, SNP-containing nucleic acid molecules,SNP detection reagents (e.g., probes and primers),oligonucleotides/polynucleotides include PNA oligomers and other nucleicacid analogs. Other examples of nucleic acid analogs andalternative/modified nucleic acid chemistries known in the art aredescribed in Current Protocols in Nucleic Acid Chemistry, John Wiley &Sons, N.Y. (2002).

The present invention further provides nucleic acid molecules thatencode fragments of the variant polypeptides disclosed herein as well asnucleic acid molecules that encode obvious variants of such variantpolypeptides. Such nucleic acid molecules may be naturally occurring,such as paralogs (different locus) and orthologs (different organism),or may be constructed by recombinant DNA methods or by chemicalsynthesis. Non-naturally occurring variants may be made by mutagenesistechniques, including those applied to nucleic acid molecules, cells, ororganisms. Accordingly, the variants can contain nucleotidesubstitutions, deletions, inversions and insertions (in addition to theSNPs disclosed in Tables 1 and 2). Variation can occur in either or boththe coding and non-coding regions. The variations can produceconservative and/or non-conservative amino acid substitutions.

Further variants of the nucleic acid molecules disclosed in Tables 1 and2, such as naturally occurring allelic variants (as well as orthologsand paralogs) and synthetic variants produced by mutagenesis techniques,can be identified and/or produced using methods well known in the art.Such further variants can comprise a nucleotide sequence that shares atleast 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or99% sequence identity with a nucleic acid sequence disclosed in Table 1and/or Table 2 (or a fragment thereof) and that includes a novel SNPallele disclosed in Table 1 and/or Table 2. Further, variants cancomprise a nucleotide sequence that encodes a polypeptide that shares atleast 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or99% sequence identity with a polypeptide sequence disclosed in Table 1(or a fragment thereof) and that includes a novel SNP allele disclosedin Table 1 and/or Table 2. Thus, an aspect of the present invention thatis specifically contemplated are isolated nucleic acid molecules thathave a certain degree of sequence variation compared with the sequencesshown in Tables 1-2, but that contain a novel SNP allele disclosedherein. In other words, as long as an isolated nucleic acid moleculecontains a novel SNP allele disclosed herein, other portions of thenucleic acid molecule that flank the novel SNP allele can vary to somedegree from the specific transcript, genomic, and context sequencesreferred to and shown in Tables 1 and 2, and can encode a polypeptidethat varies to some degree from the specific polypeptide sequencesreferred to in Table 1.

To determine the percent identity of two amino acid sequences or twonucleotide sequences of two molecules that share sequence homology, thesequences are aligned for optimal comparison purposes (e.g., gaps can beintroduced in one or both of a first and a second amino acid or nucleicacid sequence for optimal alignment and non-homologous sequences can bedisregarded for comparison purposes). In a preferred embodiment, atleast 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more of the length of areference sequence is aligned for comparison purposes. The amino acidresidues or nucleotides at corresponding amino acid positions ornucleotide positions are then compared. When a position in the firstsequence is occupied by the same amino acid residue or nucleotide as thecorresponding position in the second sequence, then the molecules areidentical at that position (as used herein, amino acid or nucleic acid“identity” is equivalent to amino acid or nucleic acid “homology”). Thepercent identity between the two sequences is a function of the numberof identical positions shared by the sequences, taking into account thenumber of gaps, and the length of each gap, which need to be introducedfor optimal alignment of the two sequences.

The comparison of sequences and determination of percent identitybetween two sequences can be accomplished using a mathematicalalgorithm. Computational Molecular Biology, A. M. Lesk, ed., OxfordUniversity Press, N.Y. (1988); Biocomputing: Informatics and GenomeProjects, D. W. Smith, ed., Academic Press, N.Y. (1993); ComputerAnalysis of Sequence Data, Part 1, A. M. Griffin and H. G. Griffin,eds., Humana Press, N.J. (1994); Sequence Analysis in Molecular Biology,G. von Heinje, ed., Academic Press, N.Y. (1987); and Sequence AnalysisPrimer, M. Gribskov and J. Devereux, eds., M. Stockton Press, N.Y.(1991). In a preferred embodiment, the percent identity between twoamino acid sequences is determined using the Needleman and Wunschalgorithm (J Mol Biol (48):444-453 (1970)) which has been incorporatedinto the GAP program in the GCG software package, using either a Blossom62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6,or 4 and a length weight of 1, 2, 3, 4, 5, or 6.

In yet another preferred embodiment, the percent identity between twonucleotide sequences is determined using the GAP program in the GCGsoftware package using a NWSgapdna.CMP matrix and a gap weight of 40,50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. J.Devereux et al., Nucleic Acids Res. 12(1):387 (1984). In anotherembodiment, the percent identity between two amino acid or nucleotidesequences is determined using the algorithm of E. Myers and W. Miller(CABIOS 4:11-17 (1989)) which has been incorporated into the ALIGNprogram (version 2.0), using a PAM120 weight residue table, a gap lengthpenalty of 12, and a gap penalty of 4.

The nucleotide and amino acid sequences of the present invention canfurther be used as a “query sequence” to perform a search againstsequence databases; for example, to identify other family members orrelated sequences. Such searches can be performed using the NBLAST andXBLAST programs (version 2.0). Altschul et al., J Mol Biol 215:403-10(1990). BLAST nucleotide searches can be performed with the NBLASTprogram, score=100, wordlength=12 to obtain nucleotide sequenceshomologous to the nucleic acid molecules of the invention. BLAST proteinsearches can be performed with the XBLAST program, score=50,wordlength=3 to obtain amino acid sequences homologous to the proteinsof the invention. To obtain gapped alignments for comparison purposes,Gapped BLAST can be utilized. Altschul et al., Nucleic Acids Res25(17):3389-3402 (1997). When utilizing BLAST and gapped BLAST programs,the default parameters of the respective programs (e.g., XBLAST andNBLAST) can be used. In addition to BLAST, examples of other search andsequence comparison programs used in the art include, but are notlimited to, FASTA (Pearson, Methods Mol Biol 25, 365-389 (1994)) andKERR (Dufresne et al., Nat Biotechnol 20(12): 1269-71 (December 2002)).For further information regarding bioinformatics techniques, see CurrentProtocols in Bioinformatics, John Wiley & Sons, Inc., N.Y.

The present invention further provides non-coding fragments of thenucleic acid molecules disclosed in Table 1 and/or Table 2. Preferrednon-coding fragments include, but are not limited to, promotersequences, enhancer sequences, intronic sequences, 5′ untranslatedregions (UTRs), 3′ untranslated regions, gene modulating sequences andgene termination sequences. Such fragments are useful, for example, incontrolling heterologous gene expression and in developing screens toidentify gene-modulating agents.

SNP Detection Reagents

In a specific aspect of the present invention, the SNPs disclosed inTable 1 and/or Table 2, and their associated transcript sequences(referred to in Table 1 as SEQ ID NOS:1-84), genomic sequences (referredto in Table 2 as SEQ ID NOS:338-500), and context sequences(transcript-based context sequences are referred to in Table 1 as SEQ IDNOS:169-337; genomic-based context sequences are provided in Table 2 asSEQ ID NOS:501-3098), can be used for the design of SNP detectionreagents. The actual sequences referred to in the tables are provided inthe Sequence Listing. As used herein, a “SNP detection reagent” is areagent that specifically detects a specific target SNP positiondisclosed herein, and that is preferably specific for a particularnucleotide (allele) of the target SNP position (i.e., the detectionreagent preferably can differentiate between different alternativenucleotides at a target SNP position, thereby allowing the identity ofthe nucleotide present at the target SNP position to be determined).Typically, such detection reagent hybridizes to a target SNP-containingnucleic acid molecule by complementary base-pairing in a sequencespecific manner, and discriminates the target variant sequence fromother nucleic acid sequences such as an art-known form in a test sample.An example of a detection reagent is a probe that hybridizes to a targetnucleic acid containing one or more of the SNPs referred to in Table 1and/or Table 2. In a preferred embodiment, such a probe candifferentiate between nucleic acids having a particular nucleotide(allele) at a target SNP position from other nucleic acids that have adifferent nucleotide at the same target SNP position. In addition, adetection reagent may hybridize to a specific region 5′ and/or 3′ to aSNP position, particularly a region corresponding to the contextsequences referred to in Table 1 and/or Table 2 (transcript-basedcontext sequences are referred to in Table 1 as SEQ ID NOS:169-337;genomic-based context sequences are referred to in Table 2 as SEQ IDNOS:501-3098). Another example of a detection reagent is a primer thatacts as an initiation point of nucleotide extension along acomplementary strand of a target polynucleotide. The SNP sequenceinformation provided herein is also useful for designing primers, e.g.allele-specific primers, to amplify (e.g., using PCR) any SNP of thepresent invention.

In one preferred embodiment of the invention, a SNP detection reagent isan isolated or synthetic DNA or RNA polynucleotide probe or primer orPNA oligomer, or a combination of DNA, RNA and/or PNA, that hybridizesto a segment of a target nucleic acid molecule containing a SNPidentified in Table 1 and/or Table 2. A detection reagent in the form ofa polynucleotide may optionally contain modified base analogs,intercalators or minor groove binders. Multiple detection reagents suchas probes may be, for example, affixed to a solid support (e.g., arraysor beads) or supplied in solution (e.g. probe/primer sets for enzymaticreactions such as PCR, RT-PCR, TaqMan assays, or primer-extensionreactions) to form a SNP detection kit.

A probe or primer typically is a substantially purified oligonucleotideor PNA oligomer. Such oligonucleotide typically comprises a region ofcomplementary nucleotide sequence that hybridizes under stringentconditions to at least about 8, 10, 12, 16, 18, 20, 22, 25, 30, 40, 50,55, 60, 65, 70, 80, 90, 100, 120 (or any other number in-between) ormore consecutive nucleotides in a target nucleic acid molecule.Depending on the particular assay, the consecutive nucleotides caneither include the target SNP position, or be a specific region in closeenough proximity 5′ and/or 3′ to the SNP position to carry out thedesired assay.

Other preferred primer and probe sequences can readily be determinedusing the transcript sequences (SEQ ID NOS:1-84), genomic sequences (SEQID NOS:338-500), and SNP context sequences (transcript-based contextsequences are referred to in Table 1 as SEQ ID NOS:169-337;genomic-based context sequences are referred to in Table 2 as SEQ IDNOS:501-3098) disclosed in the Sequence Listing and in Tables 1 and 2.The actual sequences referred to in the tables are provided in theSequence Listing. It will be apparent to one of skill in the art thatsuch primers and probes are directly useful as reagents for genotypingthe SNPs of the present invention, and can be incorporated into anykit/system format.

In order to produce a probe or primer specific for a targetSNP-containing sequence, the gene/transcript and/or context sequencesurrounding the SNP of interest is typically examined using a computeralgorithm that starts at the 5′ or at the 3′ end of the nucleotidesequence. Typical algorithms will then identify oligomers of definedlength that are unique to the gene/SNP context sequence, have a GCcontent within a range suitable for hybridization, lack predictedsecondary structure that may interfere with hybridization, and/orpossess other desired characteristics or that lack other undesiredcharacteristics.

A primer or probe of the present invention is typically at least about 8nucleotides in length. In one embodiment of the invention, a primer or aprobe is at least about 10 nucleotides in length. In a preferredembodiment, a primer or a probe is at least about 12 nucleotides inlength. In a more preferred embodiment, a primer or probe is at leastabout 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 nucleotides in length.While the maximal length of a probe can be as long as the targetsequence to be detected, depending on the type of assay in which it isemployed, it is typically less than about 50, 60, 65, or 70 nucleotidesin length. In the case of a primer, it is typically less than about 30nucleotides in length. In a specific preferred embodiment of theinvention, a primer or a probe is within the length of about 18 andabout 28 nucleotides. However, in other embodiments, such as nucleicacid arrays and other embodiments in which probes are affixed to asubstrate, the probes can be longer, such as on the order of 30-70, 75,80, 90, 100, or more nucleotides in length (see the section belowentitled “SNP Detection Kits and Systems”).

For analyzing SNPs, it may be appropriate to use oligonucleotidesspecific for alternative SNP alleles. Such oligonucleotides that detectsingle nucleotide variations in target sequences may be referred to bysuch terms as “allele-specific oligonucleotides,” “allele-specificprobes,” or “allele-specific primers.” The design and use ofallele-specific probes for analyzing polymorphisms is described in,e.g., Mutation Detection: A Practical Approach, Cotton et al., eds.,Oxford University Press (1998); Saiki et al., Nature 324:163-166 (1986);Dattagupta, EP235,726; and Saiki, WO 89/11548.

While the design of each allele-specific primer or probe depends onvariables such as the precise composition of the nucleotide sequencesflanking a SNP position in a target nucleic acid molecule, and thelength of the primer or probe, another factor in the use of primers andprobes is the stringency of the condition under which the hybridizationbetween the probe or primer and the target sequence is performed. Higherstringency conditions utilize buffers with lower ionic strength and/or ahigher reaction temperature, and tend to require a more perfect matchbetween probe/primer and a target sequence in order to form a stableduplex. If the stringency is too high, however, hybridization may notoccur at all. In contrast, lower stringency conditions utilize bufferswith higher ionic strength and/or a lower reaction temperature, andpermit the formation of stable duplexes with more mismatched basesbetween a probe/primer and a target sequence. By way of example and notlimitation, exemplary conditions for high stringency hybridizationconditions using an allele-specific probe are as follows:prehybridization with a solution containing 5× standard saline phosphateEDTA (SSPE), 0.5% NaDodSO₄ (SDS) at 55° C., and incubating probe withtarget nucleic acid molecules in the same solution at the sametemperature, followed by washing with a solution containing 2×SSPE, and0.1% SDS at 55° C. or room temperature.

Moderate stringency hybridization conditions may be used forallele-specific primer extension reactions with a solution containing,e.g., about 50 mM KCl at about 46° C. Alternatively, the reaction may becarried out at an elevated temperature such as 60° C. In anotherembodiment, a moderately stringent hybridization condition suitable foroligonucleotide ligation assay (OLA) reactions wherein two probes areligated if they are completely complementary to the target sequence mayutilize a solution of about 100 mM KCl at a temperature of 46° C.

In a hybridization-based assay, allele-specific probes can be designedthat hybridize to a segment of target DNA from one individual but do nothybridize to the corresponding segment from another individual due tothe presence of different polymorphic forms (e.g., alternative SNPalleles/nucleotides) in the respective DNA segments from the twoindividuals. Hybridization conditions should be sufficiently stringentthat there is a significant detectable difference in hybridizationintensity between alleles, and preferably an essentially binaryresponse, whereby a probe hybridizes to only one of the alleles orsignificantly more strongly to one allele. While a probe may be designedto hybridize to a target sequence that contains a SNP site such that theSNP site aligns anywhere along the sequence of the probe, the probe ispreferably designed to hybridize to a segment of the target sequencesuch that the SNP site aligns with a central position of the probe(e.g., a position within the probe that is at least three nucleotidesfrom either end of the probe). This design of probe generally achievesgood discrimination in hybridization between different allelic forms.

In another embodiment, a probe or primer may be designed to hybridize toa segment of target DNA such that the SNP aligns with either the 5′ mostend or the 3′ most end of the probe or primer. In a specific preferredembodiment that is particularly suitable for use in a oligonucleotideligation assay (U.S. Pat. No. 4,988,617), the 3′most nucleotide of theprobe aligns with the SNP position in the target sequence.

Oligonucleotide probes and primers may be prepared by methods well knownin the art. Chemical synthetic methods include, but are not limited to,the phosphotriester method described by Narang et al., Methods inEnzymology 68:90 (1979); the phosphodiester method described by Brown etal., Methods in Enzymology 68:109 (1979); the diethylphosphoamidatemethod described by Beaucage et al., Tetrahedron Letters 22:1859 (1981);and the solid support method described in U.S. Pat. No. 4,458,066.

Allele-specific probes are often used in pairs (or, less commonly, insets of 3 or 4, such as if a SNP position is known to have 3 or 4alleles, respectively, or to assay both strands of a nucleic acidmolecule for a target SNP allele), and such pairs may be identicalexcept for a one nucleotide mismatch that represents the allelicvariants at the SNP position. Commonly, one member of a pair perfectlymatches a reference form of a target sequence that has a more common SNPallele (i.e., the allele that is more frequent in the target population)and the other member of the pair perfectly matches a form of the targetsequence that has a less common SNP allele (i.e., the allele that israrer in the target population). In the case of an array, multiple pairsof probes can be immobilized on the same support for simultaneousanalysis of multiple different polymorphisms.

In one type of PCR-based assay, an allele-specific primer hybridizes toa region on a target nucleic acid molecule that overlaps a SNP positionand only primes amplification of an allelic form to which the primerexhibits perfect complementarity. Gibbs, Nucleic Acid Res 17:2427-2448(1989). Typically, the primer's 3′-most nucleotide is aligned with andcomplementary to the SNP position of the target nucleic acid molecule.This primer is used in conjunction with a second primer that hybridizesat a distal site. Amplification proceeds from the two primers, producinga detectable product that indicates which allelic form is present in thetest sample. A control is usually performed with a second pair ofprimers, one of which shows a single base mismatch at the polymorphicsite and the other of which exhibits perfect complementarity to a distalsite. The single-base mismatch prevents amplification or substantiallyreduces amplification efficiency, so that either no detectable productis formed or it is formed in lower amounts or at a slower pace. Themethod generally works most effectively when the mismatch is at the3′-most position of the oligonucleotide (i.e., the 3′-most position ofthe oligonucleotide aligns with the target SNP position) because thisposition is most destabilizing to elongation from the primer (see, e.g.,WO 93/22456). This PCR-based assay can be utilized as part of the TaqManassay, described below.

In a specific embodiment of the invention, a primer of the inventioncontains a sequence substantially complementary to a segment of a targetSNP-containing nucleic acid molecule except that the primer has amismatched nucleotide in one of the three nucleotide positions at the3′-most end of the primer, such that the mismatched nucleotide does notbase pair with a particular allele at the SNP site. In a preferredembodiment, the mismatched nucleotide in the primer is the second fromthe last nucleotide at the 3′-most position of the primer. In a morepreferred embodiment, the mismatched nucleotide in the primer is thelast nucleotide at the 3′-most position of the primer.

In another embodiment of the invention, a SNP detection reagent of theinvention is labeled with a fluorogenic reporter dye that emits adetectable signal. While the preferred reporter dye is a fluorescentdye, any reporter dye that can be attached to a detection reagent suchas an oligonucleotide probe or primer is suitable for use in theinvention. Such dyes include, but are not limited to, Acridine, AMCA,BODIPY, Cascade Blue, Cy2, Cy3, Cy5, Cy7, Dabcyl, Edans, Eosin,Erythrosin, Fluorescein, 6-Fam, Tet, Joe, Hex, Oregon Green, Rhodamine,Rhodol Green, Tamra, Rox, and Texas Red.

In yet another embodiment of the invention, the detection reagent may befurther labeled with a quencher dye such as Tamra, especially when thereagent is used as a self-quenching probe such as a TaqMan (U.S. Pat.Nos. 5,210,015 and 5,538,848) or Molecular Beacon probe (U.S. Pat. Nos.5,118,801 and 5,312,728), or other stemless or linear beacon probe(Livak et al., PCR Method Appl 4:357-362 (1995); Tyagi et al., NatureBiotechnology 14:303-308 (1996); Nazarenko et al., Nucl Acids Res25:2516-2521 (1997); U.S. Pat. Nos. 5,866,336 and 6,117,635.

The detection reagents of the invention may also contain other labels,including but not limited to, biotin for streptavidin binding, haptenfor antibody binding, and oligonucleotide for binding to anothercomplementary oligonucleotide such as pairs of zipcodes.

The present invention also contemplates reagents that do not contain (orthat are complementary to) a SNP nucleotide identified herein but thatare used to assay one or more SNPs disclosed herein. For example,primers that flank, but do not hybridize directly to a target SNPposition provided herein are useful in primer extension reactions inwhich the primers hybridize to a region adjacent to the target SNPposition (i.e., within one or more nucleotides from the target SNPsite). During the primer extension reaction, a primer is typically notable to extend past a target SNP site if a particular nucleotide(allele) is present at that target SNP site, and the primer extensionproduct can be detected in order to determine which SNP allele ispresent at the target SNP site. For example, particular ddNTPs aretypically used in the primer extension reaction to terminate primerextension once a ddNTP is incorporated into the extension product (aprimer extension product which includes a ddNTP at the 3′-most end ofthe primer extension product, and in which the ddNTP is a nucleotide ofa SNP disclosed herein, is a composition that is specificallycontemplated by the present invention). Thus, reagents that bind to anucleic acid molecule in a region adjacent to a SNP site and that areused for assaying the SNP site, even though the bound sequences do notnecessarily include the SNP site itself, are also contemplated by thepresent invention.

SNP Detection Kits and Systems

A person skilled in the art will recognize that, based on the SNP andassociated sequence information disclosed herein, detection reagents canbe developed and used to assay any SNP of the present inventionindividually or in combination, and such detection reagents can bereadily incorporated into one of the established kit or system formatswhich are well known in the art. The terms “kits” and “systems,” as usedherein in the context of SNP detection reagents, are intended to referto such things as combinations of multiple SNP detection reagents, orone or more SNP detection reagents in combination with one or more othertypes of elements or components (e.g., other types of biochemicalreagents, containers, packages such as packaging intended for commercialsale, substrates to which SNP detection reagents are attached,electronic hardware components, etc.). Accordingly, the presentinvention further provides SNP detection kits and systems, including butnot limited to, packaged probe and primer sets (e.g. TaqMan probe/primersets), arrays/microarrays of nucleic acid molecules, and beads thatcontain one or more probes, primers, or other detection reagents fordetecting one or more SNPs of the present invention. The kits/systemscan optionally include various electronic hardware components; forexample, arrays (“DNA chips”) and microfluidic systems (“lab-on-a-chip”systems) provided by various manufacturers typically comprise hardwarecomponents. Other kits/systems (e.g., probe/primer sets) may not includeelectronic hardware components, but may be comprised of, for example,one or more SNP detection reagents (along with, optionally, otherbiochemical reagents) packaged in one or more containers.

In some embodiments, a SNP detection kit typically contains one or moredetection reagents and other components (e.g. a buffer, enzymes such asDNA polymerases or ligases, chain extension nucleotides such asdeoxynucleotide triphosphates, and in the case of Sanger-type DNAsequencing reactions, chain terminating nucleotides, positive controlsequences, negative control sequences, and the like) necessary to carryout an assay or reaction, such as amplification and/or detection of aSNP-containing nucleic acid molecule. A kit may further contain meansfor determining the amount of a target nucleic acid, and means forcomparing the amount with a standard, and can comprise instructions forusing the kit to detect the SNP-containing nucleic acid molecule ofinterest. In one embodiment of the present invention, kits are providedwhich contain the necessary reagents to carry out one or more assays todetect one or more SNPs disclosed herein. In a preferred embodiment ofthe present invention, SNP detection kits/systems are in the form ofnucleic acid arrays, or compartmentalized kits, includingmicrofluidic/lab-on-a-chip systems.

Exemplary kits of the invention can comprise a container containing aSNP detection reagent which detects a SNP disclosed herein, saidcontainer can optionally be enclosed in a package (e.g., a box forcommercial sale), and said package can further include other containerscontaining any or all of the following: enzyme (e.g., polymerase orligase, any of which can be thermostable), dNTPs and/or ddNTPs (whichcan optionally be detectably labeled, such as with a fluorescent labelor mass tag, and such label can optionally differ between any of thedATPs, dCTPs, dGTPs, dTTPs, ddATPs, ddCTPs, ddGTPs, and/or ddTTPs, sothat each of these dNTPs and/or ddNTPs can be distinguished from eachother by detection of the label, and any of these dNTPs and/or ddNTPscan optionally be stored in the same container or each in separatecontainers), buffer, controls (e.g., positive control nucleic acid, or anegative control), reagent(s) for extracting nucleic acid from a testsample, and instructions for using the kit (such as instructions forcorrelating the presence or absence of a particular allele or genotypewith an increased or decreased risk for disease such as VT, or anincreased or decreased likelihood of responding to a drug such as astatin). The SNP detection reagent can comprise, for example, at leastone primer and/or probe, any of which can optionally be allele-specific,and any of which can optionally be detectably labeled (e.g., with afluorescent label).

SNP detection kits/systems may contain, for example, one or more probes,or pairs of probes, that hybridize to a nucleic acid molecule at or neareach target SNP position. Multiple pairs of allele-specific probes maybe included in the kit/system to simultaneously assay large numbers ofSNPs, at least one of which is a SNP of the present invention. In somekits/systems, the allele-specific probes are immobilized to a substratesuch as an array or bead. For example, the same substrate can compriseallele-specific probes for detecting at least 1; 10; 100; 1000; 10,000;100,000 (or any other number in-between) or substantially all of theSNPs shown in Table 1 and/or Table 2.

The terms “arrays,” “microarrays,” and “DNA chips” are used hereininterchangeably to refer to an array of distinct polynucleotides affixedto a substrate, such as glass, plastic, paper, nylon or other type ofmembrane, filter, chip, or any other suitable solid support. Thepolynucleotides can be synthesized directly on the substrate, orsynthesized separate from the substrate and then affixed to thesubstrate. In one embodiment, the microarray is prepared and usedaccording to the methods described in Chee et al., U.S. Pat. No.5,837,832 and PCT application WO95/11995; D. J. Lockhart et al., NatBiotech 14:1675-1680 (1996); and M. Schena et al., Proc Natl Acad Sci93:10614-10619 (1996), all of which are incorporated herein in theirentirety by reference. In other embodiments, such arrays are produced bythe methods described by Brown et al., U.S. Pat. No. 5,807,522.

Nucleic acid arrays are reviewed in the following references: Zammatteoet al., “New chips for molecular biology and diagnostics,” BiotechnolAnnu Rev 8:85-101 (2002); Sosnowski et al., “Active microelectronicarray system for DNA hybridization, genotyping and pharmacogenomicapplications,” Psychiatr Genet 12(4):181-92 (December 2002); Heller,“DNA microarray technology: devices, systems, and applications,” AnnuRev Biomed Eng 4:129-53 (2002); Epub Mar. 22, 2002; Kolchinsky et al.,“Analysis of SNPs and other genomic variations using gel-based chips,”Hum Mutat 19(4):343-60 (April 2002); and McGall et al., “High-densitygenechip oligonucleotide probe arrays,” Adv Biochem Eng Biotechnol77:21-42 (2002).

Any number of probes, such as allele-specific probes, may be implementedin an array, and each probe or pair of probes can hybridize to adifferent SNP position. In the case of polynucleotide probes, they canbe synthesized at designated areas (or synthesized separately and thenaffixed to designated areas) on a substrate using a light-directedchemical process. Each DNA chip can contain, for example, thousands tomillions of individual synthetic polynucleotide probes arranged in agrid-like pattern and miniaturized (e.g., to the size of a dime).Preferably, probes are attached to a solid support in an ordered,addressable array.

A microarray can be composed of a large number of unique,single-stranded polynucleotides, usually either synthetic antisensepolynucleotides or fragments of cDNAs, fixed to a solid support. Typicalpolynucleotides are preferably about 6-60 nucleotides in length, morepreferably about 15-30 nucleotides in length, and most preferably about18-25 nucleotides in length. For certain types of microarrays or otherdetection kits/systems, it may be preferable to use oligonucleotidesthat are only about 7-20 nucleotides in length. In other types ofarrays, such as arrays used in conjunction with chemiluminescentdetection technology, preferred probe lengths can be, for example, about15-80 nucleotides in length, preferably about 50-70 nucleotides inlength, more preferably about 55-65 nucleotides in length, and mostpreferably about 60 nucleotides in length. The microarray or detectionkit can contain polynucleotides that cover the known 5′ or 3′ sequenceof a gene/transcript or target SNP site, sequential polynucleotides thatcover the full-length sequence of a gene/transcript; or uniquepolynucleotides selected from particular areas along the length of atarget gene/transcript sequence, particularly areas corresponding to oneor more SNPs disclosed in Table 1 and/or Table 2. Polynucleotides usedin the microarray or detection kit can be specific to a SNP or SNPs ofinterest (e.g., specific to a particular SNP allele at a target SNPsite, or specific to particular SNP alleles at multiple different SNPsites), or specific to a polymorphic gene/transcript orgenes/transcripts of interest.

Hybridization assays based on polynucleotide arrays rely on thedifferences in hybridization stability of the probes to perfectlymatched and mismatched target sequence variants. For SNP genotyping, itis generally preferable that stringency conditions used in hybridizationassays are high enough such that nucleic acid molecules that differ fromone another at as little as a single SNP position can be differentiated(e.g., typical SNP hybridization assays are designed so thathybridization will occur only if one particular nucleotide is present ata SNP position, but will not occur if an alternative nucleotide ispresent at that SNP position). Such high stringency conditions may bepreferable when using, for example, nucleic acid arrays ofallele-specific probes for SNP detection. Such high stringencyconditions are described in the preceding section, and are well known tothose skilled in the art and can be found in, for example, CurrentProtocols in Molecular Biology 6.3.1-6.3.6, John Wiley & Sons, N.Y.(1989).

In other embodiments, the arrays are used in conjunction withchemiluminescent detection technology. The following patents and patentapplications, which are all hereby incorporated by reference, provideadditional information pertaining to chemiluminescent detection. U.S.patent applications that describe chemiluminescent approaches formicroarray detection: Ser. No. 10/620,332 and 10/620,333. U.S. patentsthat describe methods and compositions of dioxetane for performingchemiluminescent detection: U.S. Pat. Nos. 6,124,478; 6,107,024;5,994,073; 5,981,768; 5,871,938; 5,843,681; 5,800,999 and 5,773,628. Andthe U.S. published application that discloses methods and compositionsfor microarray controls: US2002/0110828.

In one embodiment of the invention, a nucleic acid array can comprise anarray of probes of about 15-25 nucleotides in length. In furtherembodiments, a nucleic acid array can comprise any number of probes, inwhich at least one probe is capable of detecting one or more SNPsdisclosed in Table 1 and/or Table 2, and/or at least one probe comprisesa fragment of one of the sequences selected from the group consisting ofthose disclosed in Table 1, Table 2, the Sequence Listing, and sequencescomplementary thereto, said fragment comprising at least about 8consecutive nucleotides, preferably 10, 12, 15, 16, 18, 20, morepreferably 22, 25, 30, 40, 47, 50, 55, 60, 65, 70, 80, 90, 100, or moreconsecutive nucleotides (or any other number in-between) and containing(or being complementary to) a novel SNP allele disclosed in Table 1and/or Table 2. In some embodiments, the nucleotide complementary to theSNP site is within 5, 4, 3, 2, or 1 nucleotide from the center of theprobe, more preferably at the center of said probe.

A polynucleotide probe can be synthesized on the surface of thesubstrate by using a chemical coupling procedure and an ink jetapplication apparatus, as described in PCT application WO95/251116(Baldeschweiler et al.) which is incorporated herein in its entirety byreference. In another aspect, a “gridded” array analogous to a dot (orslot) blot may be used to arrange and link cDNA fragments oroligonucleotides to the surface of a substrate using a vacuum system,thermal, UV, mechanical or chemical bonding procedures. An array, suchas those described above, may be produced by hand or by using availabledevices (slot blot or dot blot apparatus), materials (any suitable solidsupport), and machines (including robotic instruments), and may contain8, 24, 96, 384, 1536, 6144 or more polynucleotides, or any other numberwhich lends itself to the efficient use of commercially availableinstrumentation.

Using such arrays or other kits/systems, the present invention providesmethods of identifying the SNPs disclosed herein in a test sample. Suchmethods typically involve incubating a test sample of nucleic acids withan array comprising one or more probes corresponding to at least one SNPposition of the present invention, and assaying for binding of a nucleicacid from the test sample with one or more of the probes. Conditions forincubating a SNP detection reagent (or a kit/system that employs one ormore such SNP detection reagents) with a test sample vary. Incubationconditions depend on such factors as the format employed in the assay,the detection methods employed, and the type and nature of the detectionreagents used in the assay. One skilled in the art will recognize thatany one of the commonly available hybridization, amplification and arrayassay formats can readily be adapted to detect the SNPs disclosedherein.

A SNP detection kit/system of the present invention may includecomponents that are used to prepare nucleic acids from a test sample forthe subsequent amplification and/or detection of a SNP-containingnucleic acid molecule. Such sample preparation components can be used toproduce nucleic acid extracts (including DNA and/or RNA), proteins ormembrane extracts from any bodily fluids (such as blood, serum, plasma,urine, saliva, phlegm, gastric juices, semen, tears, sweat, etc.), skin,hair, cells (especially nucleated cells) such as buccal cells (e.g., asobtained by buccal swabs), biopsies, or tissue specimens. The testsamples used in the above-described methods will vary based on suchfactors as the assay format, nature of the detection method, and thespecific tissues, cells or extracts used as the test sample to beassayed. Methods of preparing nucleic acids, proteins, and cell extractsare well known in the art and can be readily adapted to obtain a samplethat is compatible with the system utilized. Automated samplepreparation systems for extracting nucleic acids from a test sample arecommercially available, and examples are Qiagen's BioRobot 9600, AppliedBiosystems' PRISM™ 6700 sample preparation system, and Roche MolecularSystems' COBAS AmpliPrep System.

Another form of kit contemplated by the present invention is acompartmentalized kit. A compartmentalized kit includes any kit in whichreagents are contained in separate containers. Such containers include,for example, small glass containers, plastic containers, strips ofplastic, glass or paper, or arraying material such as silica. Suchcontainers allow one to efficiently transfer reagents from onecompartment to another compartment such that the test samples andreagents are not cross-contaminated, or from one container to anothervessel not included in the kit, and the agents or solutions of eachcontainer can be added in a quantitative fashion from one compartment toanother or to another vessel. Such containers may include, for example,one or more containers which will accept the test sample, one or morecontainers which contain at least one probe or other SNP detectionreagent for detecting one or more SNPs of the present invention, one ormore containers which contain wash reagents (such as phosphate bufferedsaline, Tris-buffers, etc.), and one or more containers which containthe reagents used to reveal the presence of the bound probe or other SNPdetection reagents. The kit can optionally further comprise compartmentsand/or reagents for, for example, nucleic acid amplification or otherenzymatic reactions such as primer extension reactions, hybridization,ligation, electrophoresis (preferably capillary electrophoresis), massspectrometry, and/or laser-induced fluorescent detection. The kit mayalso include instructions for using the kit. Exemplary compartmentalizedkits include microfluidic devices known in the art. See, e.g., Weigl etal., “Lab-on-a-chip for drug development,” Adv Drug Deliv Rev55(3):349-77 (February 2003). In such microfluidic devices, thecontainers may be referred to as, for example, microfluidic“compartments,” “chambers,” or “channels.”

Microfluidic devices, which may also be referred to as “lab-on-a-chip”systems, biomedical micro-electro-mechanical systems (bioMEMs), ormulticomponent integrated systems, are exemplary kits/systems of thepresent invention for analyzing SNPs. Such systems miniaturize andcompartmentalize processes such as probe/target hybridization, nucleicacid amplification, and capillary electrophoresis reactions in a singlefunctional device. Such microfluidic devices typically utilize detectionreagents in at least one aspect of the system, and such detectionreagents may be used to detect one or more SNPs of the presentinvention. One example of a microfluidic system is disclosed in U.S.Pat. No. 5,589,136, which describes the integration of PCR amplificationand capillary electrophoresis in chips. Exemplary microfluidic systemscomprise a pattern of microchannels designed onto a glass, silicon,quartz, or plastic wafer included on a microchip. The movements of thesamples may be controlled by electric, electroosmotic or hydrostaticforces applied across different areas of the microchip to createfunctional microscopic valves and pumps with no moving parts. Varyingthe voltage can be used as a means to control the liquid flow atintersections between the micro-machined channels and to change theliquid flow rate for pumping across different sections of the microchip.See, for example, U.S. Pat. No. 6,153,073, Dubrow et al., and U.S. Pat.No. 6,156,181, Parce et al.

For genotyping SNPs, an exemplary microfluidic system may integrate, forexample, nucleic acid amplification, primer extension, capillaryelectrophoresis, and a detection method such as laser inducedfluorescence detection. In a first step of an exemplary process forusing such an exemplary system, nucleic acid samples are amplified,preferably by PCR. Then, the amplification products are subjected toautomated primer extension reactions using ddNTPs (specific fluorescencefor each ddNTP) and the appropriate oligonucleotide primers to carry outprimer extension reactions which hybridize just upstream of the targetedSNP. Once the extension at the 3′ end is completed, the primers areseparated from the unincorporated fluorescent ddNTPs by capillaryelectrophoresis. The separation medium used in capillary electrophoresiscan be, for example, polyacrylamide, polyethyleneglycol or dextran. Theincorporated ddNTPs in the single nucleotide primer extension productsare identified by laser-induced fluorescence detection. Such anexemplary microchip can be used to process, for example, at least 96 to384 samples, or more, in parallel.

Uses of Nucleic Acid Molecules

The nucleic acid molecules of the present invention have a variety ofuses, particularly for predicting whether an individual will benefitfrom statin treatment by reducing their risk for VT in response to thestatin treatment, as well as for the diagnosis, prognosis, treatment,and prevention of VT. For example, the nucleic acid molecules of theinvention are useful for determining the likelihood of an individual whocurrently or previously has or has had VT or who is at increased riskfor developing VT (such as an individual who has not yet had VT but isat increased risk for having VT in the future) of responding totreatment (or prevention) of VT with statins (such as by reducing theirrisk of developing primary or recurrent VT in the future), predictingthe likelihood that the individual will experience toxicity or otherundesirable side effects from the statin treatment, predicting anindividual's risk for developing VT, etc. For example, the nucleic acidmolecules are useful as hybridization probes, such as for genotypingSNPs in messenger RNA, transcript, cDNA, genomic DNA, amplified DNA orother nucleic acid molecules, and for isolating full-length cDNA andgenomic clones encoding the variant peptides disclosed in Table 1 aswell as their orthologs.

A probe can hybridize to any nucleotide sequence along the entire lengthof a nucleic acid molecule referred to in Table 1 and/or Table 2.Preferably, a probe of the present invention hybridizes to a region of atarget sequence that encompasses a SNP position indicated in Table 1and/or Table 2. More preferably, a probe hybridizes to a SNP-containingtarget sequence in a sequence-specific manner such that it distinguishesthe target sequence from other nucleotide sequences which vary from thetarget sequence only by which nucleotide is present at the SNP site.Such a probe is particularly useful for detecting the presence of aSNP-containing nucleic acid in a test sample, or for determining whichnucleotide (allele) is present at a particular SNP site (i.e.,genotyping the SNP site).

A nucleic acid hybridization probe may be used for determining thepresence, level, form, and/or distribution of nucleic acid expression.The nucleic acid whose level is determined can be DNA or RNA.Accordingly, probes specific for the SNPs described herein can be usedto assess the presence, expression and/or gene copy number in a givencell, tissue, or organism. These uses are relevant for diagnosis ofdisorders involving an increase or decrease in gene expression relativeto normal levels. In vitro techniques for detection of mRNA include, forexample, Northern blot hybridizations and in situ hybridizations. Invitro techniques for detecting DNA include Southern blot hybridizationsand in situ hybridizations. Sambrook and Russell, Molecular Cloning: ALaboratory Manual, Cold Spring Harbor Press, N.Y. (2000).

Probes can be used as part of a diagnostic test kit for identifyingcells or tissues in which a variant protein is expressed, such as bymeasuring the level of a variant protein-encoding nucleic acid (e.g.,mRNA) in a sample of cells from a subject or determining if apolynucleotide contains a SNP of interest.

Thus, the nucleic acid molecules of the invention can be used ashybridization probes to detect the SNPs disclosed herein, therebydetermining the likelihood that an individual will respond positively tostatin treatment for reducing the risk of VT, or whether an individualwith the polymorphism(s) is at risk for developing VT (or has alreadydeveloped early stage VT). Detection of a SNP associated with a diseasephenotype provides a diagnostic tool for an active disease and/orgenetic predisposition to the disease.

Furthermore, the nucleic acid molecules of the invention are thereforeuseful for detecting a gene (gene information is disclosed in Table 2,for example) which contains a SNP disclosed herein and/or products ofsuch genes, such as expressed mRNA transcript molecules (transcriptinformation is disclosed in Table 1, for example), and are thus usefulfor detecting gene expression. The nucleic acid molecules can optionallybe implemented in, for example, an array or kit format for use indetecting gene expression.

The nucleic acid molecules of the invention are also useful as primersto amplify any given region of a nucleic acid molecule, particularly aregion containing a SNP identified in Table 1 and/or Table 2.

The nucleic acid molecules of the invention are also useful forconstructing recombinant vectors (described in greater detail below).Such vectors include expression vectors that express a portion of, orall of, any of the variant peptide sequences referred to in Table 1.Vectors also include insertion vectors, used to integrate into anothernucleic acid molecule sequence, such as into the cellular genome, toalter in situ expression of a gene and/or gene product. For example, anendogenous coding sequence can be replaced via homologous recombinationwith all or part of the coding region containing one or morespecifically introduced SNPs.

The nucleic acid molecules of the invention are also useful forexpressing antigenic portions of the variant proteins, particularlyantigenic portions that contain a variant amino acid sequence (e.g., anamino acid substitution) caused by a SNP disclosed in Table 1 and/orTable 2.

The nucleic acid molecules of the invention are also useful forconstructing vectors containing a gene regulatory region of the nucleicacid molecules of the present invention.

The nucleic acid molecules of the invention are also useful fordesigning ribozymes corresponding to all, or a part, of an mRNA moleculeexpressed from a SNP-containing nucleic acid molecule described herein.

The nucleic acid molecules of the invention are also useful forconstructing host cells expressing a part, or all, of the nucleic acidmolecules and variant peptides.

The nucleic acid molecules of the invention are also useful forconstructing transgenic animals expressing all, or a part, of thenucleic acid molecules and variant peptides. The production ofrecombinant cells and transgenic animals having nucleic acid moleculeswhich contain the SNPs disclosed in Table 1 and/or Table 2 allows, forexample, effective clinical design of treatment compounds and dosageregimens.

The nucleic acid molecules of the invention are also useful in assaysfor drug screening to identify compounds that, for example, modulatenucleic acid expression.

The nucleic acid molecules of the invention are also useful in genetherapy in patients whose cells have aberrant gene expression. Thus,recombinant cells, which include a patient's cells that have beenengineered ex vivo and returned to the patient, can be introduced intoan individual where the recombinant cells produce the desired protein totreat the individual.

SNP Genotyping Methods

The process of determining which nucleotide(s) is/are present at each ofone or more SNP positions (such as a SNP position disclosed in Table 1and/or Table 2), for either or both alleles, may be referred to by suchphrases as SNP genotyping, determining the “identity” of a SNP,determining the “content” of a SNP, or determining whichnucleotide(s)/allele(s) is/are present at a SNP position. Thus, theseterms can refer to detecting a single allele (nucleotide) at a SNPposition or can encompass detecting both alleles (nucleotides) at a SNPposition (such as to determine the homozygous or heterozygous state of aSNP position). Furthermore, these terms may also refer to detecting anamino acid residue encoded by a SNP (such as alternative amino acidresidues that are encoded by different codons created by alternativenucleotides at a missense SNP position, for example).

The present invention provides methods of SNP genotyping, such as foruse in implementing a preventive or treatment regimen for an individualbased on that individual having an increased susceptibility fordeveloping VT and/or an increased likelihood of benefiting from statintreatment for reducing the risk of VT, in evaluating an individual'slikelihood of responding to statin treatment (particularly for treatingor preventing VT), in selecting a treatment or preventive regimen (e.g.,in deciding whether or not to administer statin treatment to anindividual having VT, or who is at increased risk for developing VT inthe future), or in formulating or selecting a particular statin-basedtreatment or preventive regimen such as dosage and/or frequency ofadministration of statin treatment or choosing which form/type of statinto be administered, such as a particular pharmaceutical composition orcompound, etc.), determining the likelihood of experiencing toxicity orother undesirable side effects from statin treatment, or selectingindividuals for a clinical trial of a statin (e.g., selectingindividuals to participate in the trial who are most likely to respondpositively from the statin treatment and/or excluding individuals fromthe trial who are unlikely to respond positively from the statintreatment based on their SNP genotype(s), or selecting individuals whoare unlikely to respond positively to statins based on their SNPgenotype(s) to participate in a clinical trial of another type of drugthat may benefit them), etc. The SNP genotyping methods of the inventioncan also be useful for evaluating an individual's risk for developing VTand for predicting the likelihood that an individual who has previouslyhad VT will have a recurrence of VT again in the future (recurrent VT).

Nucleic acid samples can be genotyped to determine which allele(s)is/are present at any given genetic region (e.g., SNP position) ofinterest by methods well known in the art. The neighboring sequence canbe used to design SNP detection reagents such as oligonucleotide probes,which may optionally be implemented in a kit format. Exemplary SNPgenotyping methods are described in Chen et al., “Single nucleotidepolymorphism genotyping: biochemistry, protocol, cost and throughput,”Pharmacogenomics J 3(2):77-96 (2003); Kwok et al., “Detection of singlenucleotide polymorphisms,” Curr Issues Mol Biol 5(2):43-60 (April 2003);Shi, “Technologies for individual genotyping: detection of geneticpolymorphisms in drug targets and disease genes,” Am J Pharmacogenomics2(3):197-205 (2002); and Kwok, “Methods for genotyping single nucleotidepolymorphisms,” Annu Rev Genomics Hum Genet 2:235-58 (2001). Exemplarytechniques for high-throughput SNP genotyping are described inMarnellos, “High-throughput SNP analysis for genetic associationstudies,” Curr Opin Drug Discov Devel 6(3):317-21 (May 2003). Common SNPgenotyping methods include, but are not limited to, TaqMan assays,molecular beacon assays, nucleic acid arrays, allele-specific primerextension, allele-specific PCR, arrayed primer extension, homogeneousprimer extension assays, primer extension with detection by massspectrometry, pyrosequencing, multiplex primer extension sorted ongenetic arrays, ligation with rolling circle amplification, homogeneousligation, OLA (U.S. Pat. No. 4,988,167), multiplex ligation reactionsorted on genetic arrays, restriction-fragment length polymorphism,single base extension-tag assays, and the Invader assay. Such methodsmay be used in combination with detection mechanisms such as, forexample, luminescence or chemiluminescence detection, fluorescencedetection, time-resolved fluorescence detection, fluorescence resonanceenergy transfer, fluorescence polarization, mass spectrometry, andelectrical detection.

Various methods for detecting polymorphisms include, but are not limitedto, methods in which protection from cleavage agents is used to detectmismatched bases in RNA/RNA or RNA/DNA duplexes (Myers et al., Science230:1242 (1985); Cotton et al., PNAS 85:4397 (1988); and Saleeba et al.,Meth. Enzymol 217:286-295 (1992)), comparison of the electrophoreticmobility of variant and wild type nucleic acid molecules (Orita et al.,PNAS 86:2766 (1989); Cotton et al., Mutat Res 285:125-144 (1993); andHayashi et al., Genet Anal Tech Appl 9:73-79 (1992)), and assaying themovement of polymorphic or wild-type fragments in polyacrylamide gelscontaining a gradient of denaturant using denaturing gradient gelelectrophoresis (DGGE) (Myers et al., Nature 313:495 (1985)). Sequencevariations at specific locations can also be assessed by nucleaseprotection assays such as RNase and S1 protection or chemical cleavagemethods.

In a preferred embodiment, SNP genotyping is performed using the TaqManassay, which is also known as the 5′ nuclease assay (U.S. Pat. Nos.5,210,015 and 5,538,848). The TaqMan assay detects the accumulation of aspecific amplified product during PCR. The TaqMan assay utilizes anoligonucleotide probe labeled with a fluorescent reporter dye and aquencher dye. The reporter dye is excited by irradiation at anappropriate wavelength, it transfers energy to the quencher dye in thesame probe via a process called fluorescence resonance energy transfer(FRET). When attached to the probe, the excited reporter dye does notemit a signal. The proximity of the quencher dye to the reporter dye inthe intact probe maintains a reduced fluorescence for the reporter. Thereporter dye and quencher dye may be at the 5′ most and the 3′ mostends, respectively, or vice versa. Alternatively, the reporter dye maybe at the 5′ or 3′ most end while the quencher dye is attached to aninternal nucleotide, or vice versa. In yet another embodiment, both thereporter and the quencher may be attached to internal nucleotides at adistance from each other such that fluorescence of the reporter isreduced.

During PCR, the 5′ nuclease activity of DNA polymerase cleaves theprobe, thereby separating the reporter dye and the quencher dye andresulting in increased fluorescence of the reporter. Accumulation of PCRproduct is detected directly by monitoring the increase in fluorescenceof the reporter dye. The DNA polymerase cleaves the probe between thereporter dye and the quencher dye only if the probe hybridizes to thetarget SNP-containing template which is amplified during PCR, and theprobe is designed to hybridize to the target SNP site only if aparticular SNP allele is present.

Preferred TaqMan primer and probe sequences can readily be determinedusing the SNP and associated nucleic acid sequence information providedherein. A number of computer programs, such as Primer Express (AppliedBiosystems, Foster City, Calif.), can be used to rapidly obtain optimalprimer/probe sets. It will be apparent to one of skill in the art thatsuch primers and probes for detecting the SNPs of the present inventionare useful in, for example, screening individuals for their likelihoodof responding to statin treatment (i.e., benefiting from statintreatment), particularly individuals who have or are susceptible to VT,or in screening for individuals who are susceptible to developing VT.These probes and primers can be readily incorporated into a kit format.The present invention also includes modifications of the Taqman assaywell known in the art such as the use of Molecular Beacon probes (U.S.Pat. Nos. 5,118,801 and 5,312,728) and other variant formats (U.S. Pat.Nos. 5,866,336 and 6,117,635).

Another preferred method for genotyping the SNPs of the presentinvention is the use of two oligonucleotide probes in an OLA (see, e.g.,U.S. Pat. No. 4,988,617). In this method, one probe hybridizes to asegment of a target nucleic acid with its 3′ most end aligned with theSNP site. A second probe hybridizes to an adjacent segment of the targetnucleic acid molecule directly 3′ to the first probe. The two juxtaposedprobes hybridize to the target nucleic acid molecule, and are ligated inthe presence of a linking agent such as a ligase if there is perfectcomplementarity between the 3′ most nucleotide of the first probe withthe SNP site. If there is a mismatch, ligation would not occur. Afterthe reaction, the ligated probes are separated from the target nucleicacid molecule, and detected as indicators of the presence of a SNP.

The following patents, patent applications, and published internationalpatent applications, which are all hereby incorporated by reference,provide additional information pertaining to techniques for carrying outvarious types of OLA. The following U.S. patents describe OLA strategiesfor performing SNP detection: U.S. Pat. Nos. 6,027,889; 6,268,148;5,494,810; 5,830,711 and 6,054,564. WO 97/31256 and WO 00/56927 describeOLA strategies for performing SNP detection using universal arrays,wherein a zipcode sequence can be introduced into one of thehybridization probes, and the resulting product, or amplified product,hybridized to a universal zip code array. U.S. application US01/17329(and Ser. No. 09/584,905) describes OLA (or LDR) followed by PCR,wherein zipcodes are incorporated into OLA probes, and amplified PCRproducts are determined by electrophoretic or universal zipcode arrayreadout. U.S. applications 60/427,818, 60/445,636, and 60/445,494describe SNPlex methods and software for multiplexed SNP detection usingOLA followed by PCR, wherein zipcodes are incorporated into OLA probes,and amplified PCR products are hybridized with a zipchute reagent, andthe identity of the SNP determined from electrophoretic readout of thezipchute. In some embodiments, OLA is carried out prior to PCR (oranother method of nucleic acid amplification). In other embodiments, PCR(or another method of nucleic acid amplification) is carried out priorto OLA.

Another method for SNP genotyping is based on mass spectrometry. Massspectrometry takes advantage of the unique mass of each of the fournucleotides of DNA. SNPs can be unambiguously genotyped by massspectrometry by measuring the differences in the mass of nucleic acidshaving alternative SNP alleles. MALDI-TOF (Matrix Assisted LaserDesorption Ionization-Time of Flight) mass spectrometry technology ispreferred for extremely precise determinations of molecular mass, suchas SNPs. Numerous approaches to SNP analysis have been developed basedon mass spectrometry. Preferred mass spectrometry-based methods of SNPgenotyping include primer extension assays, which can also be utilizedin combination with other approaches, such as traditional gel-basedformats and microarrays.

Typically, the primer extension assay involves designing and annealing aprimer to a template PCR amplicon upstream (5′) from a target SNPposition. A mix of dideoxynucleotide triphosphates (ddNTPs) and/ordeoxynucleotide triphosphates (dNTPs) are added to a reaction mixturecontaining template (e.g., a SNP-containing nucleic acid molecule whichhas typically been amplified, such as by PCR), primer, and DNApolymerase. Extension of the primer terminates at the first position inthe template where a nucleotide complementary to one of the ddNTPs inthe mix occurs. The primer can be either immediately adjacent (i.e., thenucleotide at the 3′ end of the primer hybridizes to the nucleotide nextto the target SNP site) or two or more nucleotides removed from the SNPposition. If the primer is several nucleotides removed from the targetSNP position, the only limitation is that the template sequence betweenthe 3′ end of the primer and the SNP position cannot contain anucleotide of the same type as the one to be detected, or this willcause premature termination of the extension primer. Alternatively, ifall four ddNTPs alone, with no dNTPs, are added to the reaction mixture,the primer will always be extended by only one nucleotide, correspondingto the target SNP position. In this instance, primers are designed tobind one nucleotide upstream from the SNP position (i.e., the nucleotideat the 3′ end of the primer hybridizes to the nucleotide that isimmediately adjacent to the target SNP site on the 5′ side of the targetSNP site). Extension by only one nucleotide is preferable, as itminimizes the overall mass of the extended primer, thereby increasingthe resolution of mass differences between alternative SNP nucleotides.Furthermore, mass-tagged ddNTPs can be employed in the primer extensionreactions in place of unmodified ddNTPs. This increases the massdifference between primers extended with these ddNTPs, thereby providingincreased sensitivity and accuracy, and is particularly useful fortyping heterozygous base positions. Mass-tagging also alleviates theneed for intensive sample-preparation procedures and decreases thenecessary resolving power of the mass spectrometer.

The extended primers can then be purified and analyzed by MALDI-TOF massspectrometry to determine the identity of the nucleotide present at thetarget SNP position. In one method of analysis, the products from theprimer extension reaction are combined with light absorbing crystalsthat form a matrix. The matrix is then hit with an energy source such asa laser to ionize and desorb the nucleic acid molecules into thegas-phase. The ionized molecules are then ejected into a flight tube andaccelerated down the tube towards a detector. The time between theionization event, such as a laser pulse, and collision of the moleculewith the detector is the time of flight of that molecule. The time offlight is precisely correlated with the mass-to-charge ratio (m/z) ofthe ionized molecule. Ions with smaller m/z travel down the tube fasterthan ions with larger m/z and therefore the lighter ions reach thedetector before the heavier ions. The time-of-flight is then convertedinto a corresponding, and highly precise, m/z. In this manner, SNPs canbe identified based on the slight differences in mass, and thecorresponding time of flight differences, inherent in nucleic acidmolecules having different nucleotides at a single base position. Forfurther information regarding the use of primer extension assays inconjunction with MALDI-TOF mass spectrometry for SNP genotyping, see,e.g., Wise et al., “A standard protocol for single nucleotide primerextension in the human genome using matrix-assisted laserdesorption/ionization time-of-flight mass spectrometry,” Rapid CommunMass Spectrom 17(11):1195-202 (2003).

The following references provide further information describing massspectrometry-based methods for SNP genotyping: Bocker, “SNP and mutationdiscovery using base-specific cleavage and MALDI-TOF mass spectrometry,”Bioinformatics 19 Suppl 1:144-153 (July 2003); Storm et al., “MALDI-TOFmass spectrometry-based SNP genotyping,” Methods Mol Biol 212:241-62(2003); Jurinke et al., “The use of Mass ARRAY technology for highthroughput genotyping,” Adv Biochem Eng Biotechnol 77:57-74 (2002); andJurinke et al., “Automated genotyping using the DNA MassArraytechnology,” Methods Mol Biol 187:179-92 (2002).

SNPs can also be scored by direct DNA sequencing. A variety of automatedsequencing procedures can be utilized (e.g. Biotechniques 19:448(1995)), including sequencing by mass spectrometry. See, e.g., PCTInternational Publication No. WO 94/16101; Cohen et al., Adv Chromatogr36:127-162 (1996); and Griffin et al., Appl Biochem Biotechnol38:147-159 (1993). The nucleic acid sequences of the present inventionenable one of ordinary skill in the art to readily design sequencingprimers for such automated sequencing procedures. Commercialinstrumentation, such as the Applied Biosystems 377, 3100, 3700, 3730,and 3730xl DNA Analyzers (Foster City, Calif.), is commonly used in theart for automated sequencing.

Other methods that can be used to genotype the SNPs of the presentinvention include single-strand conformational polymorphism (SSCP), anddenaturing gradient gel electrophoresis (DGGE). Myers et al., Nature313:495 (1985). SSCP identifies base differences by alteration inelectrophoretic migration of single stranded PCR products, as describedin Orita et al., Proc. Nat. Acad. Single-stranded PCR products can begenerated by heating or otherwise denaturing double stranded PCRproducts. Single-stranded nucleic acids may refold or form secondarystructures that are partially dependent on the base sequence. Thedifferent electrophoretic mobilities of single-stranded amplificationproducts are related to base-sequence differences at SNP positions. DGGEdifferentiates SNP alleles based on the different sequence-dependentstabilities and melting properties inherent in polymorphic DNA and thecorresponding differences in electrophoretic migration patterns in adenaturing gradient gel. PCR Technology: Principles and Applications forDNA Amplification Chapter 7, Erlich, ed., W.H. Freeman and Co, N.Y.(1992).

Sequence-specific ribozymes (U.S. Pat. No. 5,498,531) can also be usedto score SNPs based on the development or loss of a ribozyme cleavagesite. Perfectly matched sequences can be distinguished from mismatchedsequences by nuclease cleavage digestion assays or by differences inmelting temperature. If the SNP affects a restriction enzyme cleavagesite, the SNP can be identified by alterations in restriction enzymedigestion patterns, and the corresponding changes in nucleic acidfragment lengths determined by gel electrophoresis.

SNP genotyping can include the steps of, for example, collecting abiological sample from a human subject (e.g., sample of tissues, cells,fluids, secretions, etc.), isolating nucleic acids (e.g., genomic DNA,mRNA or both) from the cells of the sample, contacting the nucleic acidswith one or more primers which specifically hybridize to a region of theisolated nucleic acid containing a target SNP under conditions such thathybridization and amplification of the target nucleic acid regionoccurs, and determining the nucleotide present at the SNP position ofinterest, or, in some assays, detecting the presence or absence of anamplification product (assays can be designed so that hybridizationand/or amplification will only occur if a particular SNP allele ispresent or absent). In some assays, the size of the amplificationproduct is detected and compared to the length of a control sample; forexample, deletions and insertions can be detected by a change in size ofthe amplified product compared to a normal genotype.

SNP genotyping is useful for numerous practical applications, asdescribed below. Examples of such applications include, but are notlimited to, SNP-disease association analysis, disease predispositionscreening, disease diagnosis, disease prognosis, disease progressionmonitoring, determining therapeutic strategies based on an individual'sgenotype (“pharmacogenomics”), developing therapeutic agents based onSNP genotypes associated with a disease or likelihood of responding to adrug, stratifying patient populations for clinical trials of atherapeutic, preventive, or diagnostic agent, and predicting thelikelihood that an individual will experience toxic side effects from atherapeutic agent.

Analysis of Genetic Associations Between SNPs and Phenotypic Traits

SNP genotyping for disease diagnosis, disease predisposition screening,disease prognosis, determining drug responsiveness (pharmacogenomics),drug toxicity screening, and other uses described herein, typicallyrelies on initially establishing a genetic association between one ormore specific SNPs and the particular phenotypic traits of interest.

Different study designs may be used for genetic association studies.Modern Epidemiology 609-622, Lippincott, Williams & Wilkins (1998).Observational studies are most frequently carried out in which theresponse of the patients is not interfered with. The first type ofobservational study identifies a sample of persons in whom the suspectedcause of the disease is present and another sample of persons in whomthe suspected cause is absent, and then the frequency of development ofdisease in the two samples is compared. These sampled populations arecalled cohorts, and the study is a prospective study. The other type ofobservational study is case-control or a retrospective study. In typicalcase-control studies, samples are collected from individuals with thephenotype of interest (cases) such as certain manifestations of adisease, and from individuals without the phenotype (controls) in apopulation (target population) that conclusions are to be drawn from.Then the possible causes of the disease are investigatedretrospectively. As the time and costs of collecting samples incase-control studies are considerably less than those for prospectivestudies, case-control studies are the more commonly used study design ingenetic association studies, at least during the exploration anddiscovery stage.

Case-only studies are an alternative to case-control studies whengene-environment interaction is the association of interest (Piegorschet al., “Non-hierarchical logistic models and case-only designs forassessing susceptibility in population-based case-control studies”,Statistics in Medicine 13 (1994) pp 153-162). In a typical case-onlystudy of gene-environment interaction, genotypes are obtained only fromcases who are often selected from an existing cohort study. Theassociation between genotypes and the environmental factor is thenassessed and a significant association implies that the effect of theenvironmental factor on the endpoint of interest (the case definition)differs by genotype. The primary assumption underlying the test ofassociation in case-only studies is that the environmental effect ofinterest is independent of genotype (e.g., allocation to statin therapyis independent of genotype) and it has been shown that the case-onlydesign has more power than the case-control design to detectgene-environment interaction when this assumption is true in thepopulation (Yang et al., “Sample Size Requirements in Case-Only Designsto Detect Gene-Environment Interaction”, American Journal ofEpidemiology 146:9 (1997) pp 713-720). Selecting cases from a randomizedclinical trial may be an ideal setting in which to perform a case-onlystudy since genotypes will be independent of treatment by design.

In observational studies, there may be potential confounding factorsthat should be taken into consideration. Confounding factors are thosethat are associated with both the real cause(s) of the disease and thedisease itself, and they include demographic information such as age,gender, ethnicity as well as environmental factors. When confoundingfactors are not matched in cases and controls in a study, and are notcontrolled properly, spurious association results can arise. Ifpotential confounding factors are identified, they should be controlledfor by analysis methods explained below.

In a genetic association study, the cause of interest to be tested is acertain allele or a SNP or a combination of alleles or a haplotype fromseveral SNPs. Thus, tissue specimens (e.g., whole blood) from thesampled individuals may be collected and genomic DNA genotyped for theSNP(s) of interest. In addition to the phenotypic trait of interest,other information such as demographic (e.g., age, gender, ethnicity,etc.), clinical, and environmental information that may influence theoutcome of the trait can be collected to further characterize and definethe sample set. In many cases, these factors are known to be associatedwith diseases and/or SNP allele frequencies. There are likelygene-environment and/or gene-gene interactions as well. Analysis methodsto address gene-environment and gene-gene interactions (for example, theeffects of the presence of both susceptibility alleles at two differentgenes can be greater than the effects of the individual alleles at twogenes combined) are discussed below.

After all the relevant phenotypic and genotypic information has beenobtained, statistical analyses are carried out to determine if there isany significant correlation between the presence of an allele or agenotype with the phenotypic characteristics of an individual.Preferably, data inspection and cleaning are first performed beforecarrying out statistical tests for genetic association. Epidemiologicaland clinical data of the samples can be summarized by descriptivestatistics with tables and graphs. Data validation is preferablyperformed to check for data completion, inconsistent entries, andoutliers. Chi-squared tests and t-tests (Wilcoxon rank-sum tests ifdistributions are not normal) may then be used to check for significantdifferences between cases and controls for discrete and continuousvariables, respectively. To ensure genotyping quality, Hardy-Weinbergdisequilibrium tests can be performed on cases and controls separately.Significant deviation from Hardy-Weinberg equilibrium (HWE) in bothcases and controls for individual markers can be indicative ofgenotyping errors. If HWE is violated in a majority of markers, it isindicative of population substructure that should be furtherinvestigated. Moreover, Hardy-Weinberg disequilibrium in cases only canindicate genetic association of the markers with the disease. B. Weir,Genetic Data Analysis, Sinauer (1990).

To test whether an allele of a single SNP is associated with the case orcontrol status of a phenotypic trait, one skilled in the art can compareallele frequencies in cases and controls. Standard chi-squared tests andFisher exact tests can be carried out on a 2×2 table (2 SNP alleles×2outcomes in the categorical trait of interest). To test whethergenotypes of a SNP are associated, chi-squared tests can be carried outon a 3×2 table (3 genotypes×2 outcomes). Score tests are also carriedout for genotypic association to contrast the three genotypicfrequencies (major homozygotes, heterozygotes and minor homozygotes) incases and controls, and to look for trends using 3 different modes ofinheritance, namely dominant (with contrast coefficients 2, −1, −1),additive or allelic (with contrast coefficients 1, 0, −1) and recessive(with contrast coefficients 1, 1, −2). Odds ratios for minor versusmajor alleles, and odds ratios for heterozygote and homozygote variantsversus the wild type genotypes are calculated with the desiredconfidence limits, usually 95%.

In order to control for confounders and to test for interaction andeffect modifiers, stratified analyses may be performed using stratifiedfactors that are likely to be confounding, including demographicinformation such as age, ethnicity, and gender, or an interactingelement or effect modifier, such as a known major gene (e.g., APOE forAlzheimer's disease or HLA genes for autoimmune diseases), orenvironmental factors such as smoking in lung cancer. Stratifiedassociation tests may be carried out using Cochran-Mantel-Haenszel teststhat take into account the ordinal nature of genotypes with 0, 1, and 2variant alleles. Exact tests by StatXact may also be performed whencomputationally possible. Another way to adjust for confounding effectsand test for interactions is to perform stepwise multiple logisticregression analysis using statistical packages such as SAS or R.Logistic regression is a model-building technique in which the bestfitting and most parsimonious model is built to describe the relationbetween the dichotomous outcome (for instance, getting a certain diseaseor not) and a set of independent variables (for instance, genotypes ofdifferent associated genes, and the associated demographic andenvironmental factors). The most common model is one in which the logittransformation of the odds ratios is expressed as a linear combinationof the variables (main effects) and their cross-product terms(interactions). Hosmer and Lemeshow, Applied Logistic Regression, Wiley(2000). To test whether a certain variable or interaction issignificantly associated with the outcome, coefficients in the model arefirst estimated and then tested for statistical significance of theirdeparture from zero.

In addition to performing association tests one marker at a time,haplotype association analysis may also be performed to study a numberof markers that are closely linked together. Haplotype association testscan have better power than genotypic or allelic association tests whenthe tested markers are not the disease-causing mutations themselves butare in linkage disequilibrium with such mutations. The test will even bemore powerful if the disease is indeed caused by a combination ofalleles on a haplotype (e.g., APOE is a haplotype formed by 2 SNPs thatare very close to each other). In order to perform haplotype associationeffectively, marker-marker linkage disequilibrium measures, both D′ andr², are typically calculated for the markers within a gene to elucidatethe haplotype structure. Recent studies in linkage disequilibriumindicate that SNPs within a gene are organized in block pattern, and ahigh degree of linkage disequilibrium exists within blocks and verylittle linkage disequilibrium exists between blocks. Daly et al, NatureGenetics 29:232-235 (2001). Haplotype association with the diseasestatus can be performed using such blocks once they have beenelucidated.

Haplotype association tests can be carried out in a similar fashion asthe allelic and genotypic association tests. Each haplotype in a gene isanalogous to an allele in a multi-allelic marker. One skilled in the artcan either compare the haplotype frequencies in cases and controls ortest genetic association with different pairs of haplotypes. It has beenproposed that score tests can be done on haplotypes using the program“haplo.score.” Schaid et al, Am J Hum Genet 70:425-434 (2002). In thatmethod, haplotypes are first inferred by EM algorithm and score testsare carried out with a generalized linear model (GLM) framework thatallows the adjustment of other factors.

An important decision in the performance of genetic association tests isthe determination of the significance level at which significantassociation can be declared when the P value of the tests reaches thatlevel. In an exploratory analysis where positive hits will be followedup in subsequent confirmatory testing, an unadjusted P value <0.2 (asignificance level on the lenient side), for example, may be used forgenerating hypotheses for significant association of a SNP with certainphenotypic characteristics of a disease. It is preferred that a p-value<0.05 (a significance level traditionally used in the art) is achievedin order for a SNP to be considered to have an association with adisease. It is more preferred that a p-value <0.01 (a significance levelon the stringent side) is achieved for an association to be declared.When hits are followed up in confirmatory analyses in more samples ofthe same source or in different samples from different sources,adjustment for multiple testing will be performed as to avoid excessnumber of hits while maintaining the experiment-wide error rates at0.05. While there are different methods to adjust for multiple testingto control for different kinds of error rates, a commonly used butrather conservative method is Bonferroni correction to control theexperiment-wise or family-wise error rate. Westfall et al., Multiplecomparisons and multiple tests, SAS Institute (1999). Permutation teststo control for the false discovery rates, FDR, can be more powerful.Benjamini and Hochberg, Journal of the Royal Statistical Society, SeriesB 57:1289-1300 (1995); Westfall and Young, Resampling-based MultipleTesting, Wiley (1993). Such methods to control for multiplicity would bepreferred when the tests are dependent and controlling for falsediscovery rates is sufficient as opposed to controlling for theexperiment-wise error rates.

In replication studies using samples from different populations afterstatistically significant markers have been identified in theexploratory stage, meta-analyses can then be performed by combiningevidence of different studies. Modern Epidemiology 643-673, Lippincott,Williams & Wilkins (1998). If available, association results known inthe art for the same SNPs can be included in the meta-analyses.

Since both genotyping and disease status classification can involveerrors, sensitivity analyses may be performed to see how odds ratios andp-values would change upon various estimates on genotyping and diseaseclassification error rates.

It has been well known that subpopulation-based sampling bias betweencases and controls can lead to spurious results in case-controlassociation studies when prevalence of the disease is associated withdifferent subpopulation groups. Ewens and Spielman, Am J Hum Genet62:450-458 (1995). Such bias can also lead to a loss of statisticalpower in genetic association studies. To detect populationstratification, Pritchard and Rosenberg suggested typing markers thatare unlinked to the disease and using results of association tests onthose markers to determine whether there is any populationstratification. Pritchard et al., Am J Hum Gen 65:220-228 (1999). Whenstratification is detected, the genomic control (GC) method as proposedby Devlin and Roeder can be used to adjust for the inflation of teststatistics due to population stratification. Devlin et al., Biometrics55:997-1004 (1999). The GC method is robust to changes in populationstructure levels as well as being applicable to DNA pooling designs.Devlin et al., Genet Epidem 21:273-284 (2001).

While Pritchard's method recommended using 15-20 unlinked microsatellitemarkers, it suggested using more than 30 biallelic markers to get enoughpower to detect population stratification. For the GC method, it hasbeen shown that about 60-70 biallelic markers are sufficient to estimatethe inflation factor for the test statistics due to populationstratification. Bacanu et al., Am J Hum Genet 66:1933-1944 (2000).Hence, 70 intergenic SNPs can be chosen in unlinked regions as indicatedin a genome scan. Kehoe et al., Hum Mol Genet 8:237-245 (1999).

Once individual risk factors, genetic or non-genetic, have been foundfor the predisposition to disease, the next step is to set up aclassification/prediction scheme to predict the category (for instance,disease or no-disease) that an individual will be in depending on hisgenotypes of associated SNPs and other non-genetic risk factors.Logistic regression for discrete trait and linear regression forcontinuous trait are standard techniques for such tasks. Draper andSmith, Applied Regression Analysis, Wiley (1998). Moreover, othertechniques can also be used for setting up classification. Suchtechniques include, but are not limited to, MART, CART, neural network,and discriminant analyses that are suitable for use in comparing theperformance of different methods. The Elements of Statistical Learning,Hastie, Tibshirani & Friedman, Springer (2002).

For further information about genetic association studies, see Balding,“A tutorial on statistical methods for population association studies”,Nature Reviews Genetics 7, 781 (2006).

Disease Diagnosis and Predisposition Screening

Information on association/correlation between genotypes anddisease-related phenotypes can be exploited in several ways. Forexample, in the case of a highly statistically significant associationbetween one or more SNPs with predisposition to a disease for whichtreatment is available, detection of such a genotype pattern in anindividual may justify immediate administration of treatment, or atleast the institution of regular monitoring of the individual. Detectionof the susceptibility alleles associated with serious disease in acouple contemplating having children may also be valuable to the couplein their reproductive decisions. In the case of a weaker but stillstatistically significant association between a SNP and a human disease,immediate therapeutic intervention or monitoring may not be justifiedafter detecting the susceptibility allele or SNP. Nevertheless, thesubject can be motivated to begin simple life-style changes (e.g., diet,exercise) that can be accomplished at little or no cost to theindividual but would confer potential benefits in reducing the risk ofdeveloping conditions for which that individual may have an increasedrisk by virtue of having the risk allele(s).

The SNPs of the invention may contribute to responsiveness of anindividual to statin treatment, or to the development of VT, indifferent ways. Some polymorphisms occur within a protein codingsequence and contribute to disease phenotype by affecting proteinstructure. Other polymorphisms occur in noncoding regions but may exertphenotypic effects indirectly via influence on, for example,replication, transcription, and/or translation. A single SNP may affectmore than one phenotypic trait. Likewise, a single phenotypic trait maybe affected by multiple SNPs in different genes.

As used herein, the terms “diagnose,” “diagnosis,” and “diagnostics”include, but are not limited to, any of the following: detection of VTthat an individual may presently have,predisposition/susceptibility/predictive screening (i.e., determiningwhether an individual has an increased or decreased risk of developingVT in the future), predicting recurrence of VT in an individual,determining a particular type or subclass of VT in an individual whocurrently or previously had VT, confirming or reinforcing a previouslymade diagnosis of VT, evaluating an individual's likelihood ofresponding positively to a particular treatment or therapeutic agent(i.e., benefiting) such as statin treatment (particularly treatment orprevention of VT using statins), determining or selecting a therapeuticor preventive strategy that an individual is most likely to positivelyrespond to (e.g., selecting a particular therapeutic agent such as astatin, or combination of therapeutic agents, or selecting a particularstatin from among other statins, or determining a dosing regimen orselecting a dosage formulation, etc.), classifying (orconfirming/reinforcing) an individual as a responder/non-responder (ordetermining a particular subtype of responder/non-responder) withrespect to the individual's response to a drug treatment such as statintreatment, and predicting whether a patient is likely to experiencetoxic effects from a particular treatment or therapeutic compound. Suchdiagnostic uses can be based on the SNPs individually or a uniquecombination or SNPs disclosed herein, as well as SNP haplotypes.

Haplotypes are particularly useful in that, for example, fewer SNPs canbe genotyped to determine if a particular genomic region harbors a locusthat influences a particular phenotype, such as in linkagedisequilibrium-based SNP association analysis.

Linkage disequilibrium (LD) refers to the co-inheritance of alleles(e.g., alternative nucleotides) at two or more different SNP sites atfrequencies greater than would be expected from the separate frequenciesof occurrence of each allele in a given population. The expectedfrequency of co-occurrence of two alleles that are inheritedindependently is the frequency of the first allele multiplied by thefrequency of the second allele. Alleles that co-occur at expectedfrequencies are said to be in “linkage equilibrium.” In contrast, LDrefers to any non-random genetic association between allele(s) at two ormore different SNP sites, which is generally due to the physicalproximity of the two loci along a chromosome. LD can occur when two ormore SNPs sites are in close physical proximity to each other on a givenchromosome and therefore alleles at these SNP sites will tend to remainunseparated for multiple generations with the consequence that aparticular nucleotide (allele) at one SNP site will show a non-randomassociation with a particular nucleotide (allele) at a different SNPsite located nearby. Hence, genotyping one of the SNP sites will givealmost the same information as genotyping the other SNP site that is inLD.

Various degrees of LD can be encountered between two or more SNPs withthe result being that some SNPs are more closely associated (i.e., instronger LD) than others. Furthermore, the physical distance over whichLD extends along a chromosome differs between different regions of thegenome, and therefore the degree of physical separation between two ormore SNP sites necessary for LD to occur can differ between differentregions of the genome.

For diagnostic purposes and similar uses, if a particular SNP site isfound to be useful for, for example, predicting an individual's responseto statin treatment or an individual's susceptibility to VT, then theskilled artisan would recognize that other SNP sites which are in LDwith this SNP site would also be useful for the same purposes. Thus,polymorphisms (e.g., SNPs and/or haplotypes) that are not the actualdisease-causing (causative) polymorphisms, but are in LD with suchcausative polymorphisms, are also useful. In such instances, thegenotype of the polymorphism(s) that is/are in LD with the causativepolymorphism is predictive of the genotype of the causative polymorphismand, consequently, predictive of the phenotype (e.g., response to statintreatment or risk for developing VT) that is influenced by the causativeSNP(s). Therefore, polymorphic markers that are in LD with causativepolymorphisms are useful as diagnostic markers, and are particularlyuseful when the actual causative polymorphism(s) is/are unknown.

Examples of polymorphisms that can be in LD with one or more causativepolymorphisms (and/or in LD with one or more polymorphisms that have asignificant statistical association with a condition) and thereforeuseful for diagnosing the same condition that the causative/associatedSNP(s) is used to diagnose, include other SNPs in the same gene,protein-coding, or mRNA transcript-coding region as thecausative/associated SNP, other SNPs in the same exon or same intron asthe causative/associated SNP, other SNPs in the same haplotype block asthe causative/associated SNP, other SNPs in the same intergenic regionas the causative/associated SNP, SNPs that are outside but near a gene(e.g., within 6 kb on either side, 5′ or 3′, of a gene boundary) thatharbors a causative/associated SNP, etc. Such useful LD SNPs can beselected from among the SNPs disclosed in Table 3, for example.

Linkage disequilibrium in the human genome is reviewed in Wall et al.,“Haplotype blocks and linkage disequilibrium in the human genome,” NatRev Genet 4(8):587-97 (August 2003); Garner et al., “On selectingmarkers for association studies: patterns of linkage disequilibriumbetween two and three diallelic loci,” Genet Epidemiol 24(1):57-67(January 2003); Ardlie et al., “Patterns of linkage disequilibrium inthe human genome,” Nat Rev Genet 3(4):299-309 (April 2002); erratum inNat Rev Genet 3(7):566 (July 2002); and Remm et al., “High-densitygenotyping and linkage disequilibrium in the human genome usingchromosome 22 as a model,” Curr Opin Chem Biol 6(1):24-30 (February2002); J. B. S. Haldane, “The combination of linkage values, and thecalculation of distances between the loci of linked factors,” J Genet8:299-309 (1919); G. Mendel, Versuche über Pflanzen-Hybriden.Verhandlungen des naturforschenden Vereines in Brünn (Proceedings of theNatural History Society of Brünn) (1866); Genes IV, B. Lewin, ed.,Oxford University Press, N.Y. (1990); D. L. Hartl and A. G. ClarkPrinciples of Population Genetics 2^(nd) ed., Sinauer Associates, Inc.,Mass. (1989); J. H. Gillespie Population Genetics: A Concise Guide.2^(nd) ed., Johns Hopkins University Press (2004); R. C. Lewontin, “Theinteraction of selection and linkage. I. General considerations;heterotic models,” Genetics 49:49-67 (1964); P. G. Hoel, Introduction toMathematical Statistics 2^(nd) ed., John Wiley & Sons, Inc., N.Y.(1954); R. R. Hudson, “Two-locus sampling distributions and theirapplication,” Genetics 159:1805-1817 (2001); A. P. Dempster, N. M.Laird, D. B. Rubin, “Maximum likelihood from incomplete data via the EMalgorithm,” J R Stat Soc 39:1-38 (1977); L. Excoffier, M. Slatkin,“Maximum-likelihood estimation of molecular haplotype frequencies in adiploid population,” Mol Biol Evol 12(5):921-927 (1995); D. A. Tregouet,S. Escolano, L. Tiret, A. Mallet, J. L. Golmard, “A new algorithm forhaplotype-based association analysis: the Stochastic-EM algorithm,” AnnHum Genet 68(Pt 2):165-177 (2004); A. D. Long and C. H. Langley C H,“The power of association studies to detect the contribution ofcandidate genetic loci to variation in complex traits,” Genome Research9:720-731 (1999); A. Agresti, Categorical Data Analysis, John Wiley &Sons, Inc., N.Y. (1990); K. Lange, Mathematical and Statistical Methodsfor Genetic Analysis, Springer-Verlag New York, Inc., N.Y. (1997); TheInternational HapMap Consortium, “The International HapMap Project,”Nature 426:789-796 (2003); The International HapMap Consortium, “Ahaplotype map of the human genome,” Nature 437:1299-1320 (2005); G. A.Thorisson, A. V. Smith, L. Krishnan, L. D. Stein, “The InternationalHapMap Project Web Site,” Genome Research 15:1591-1593 (2005); G.McVean, C. C. A. Spencer, R. Chaix, “Perspectives on human geneticvariation from the HapMap project,” PLoS Genetics 1(4):413-418 (2005);J. N. Hirschhorn, M. J. Daly, “Genome-wide association studies forcommon diseases and complex traits,” Nat Genet 6:95-108 (2005); S. J.Schrodi, “A probabilistic approach to large-scale association scans: asemi-Bayesian method to detect disease-predisposing alleles,” SAGMB4(1):31 (2005); W. Y. S. Wang, B. J. Barratt, D. G. Clayton, J. A. Todd,“Genome-wide association studies: theoretical and practical concerns,”Nat Rev Genet 6:109-118 (2005); J. K. Pritchard, M. Przeworski, “Linkagedisequilibrium in humans: models and data,” Am J Hum Genet 69:1-14(2001).

As discussed above, an aspect of the present invention relates to SNPsthat are in LD with an interrogated SNP and which can also be used asvalid markers for determining an individual's likelihood of benefitingfrom statin treatment, or whether an individual has an increased ordecreased risk of having or developing VT. As used herein, the term“interrogated SNP” refers to SNPs that have been found to be associatedwith statin response, particularly for reducing VT risk, usinggenotyping results and analysis, or other appropriate experimentalmethod as exemplified in the working examples described in thisapplication. As used herein, the term “LD SNP” refers to a SNP that hasbeen characterized as a SNP associated with statin response or anincreased or decreased risk of VT due to their being in LD with the“interrogated SNP” under the methods of calculation described in theapplication. Below, applicants describe the methods of calculation withwhich one of ordinary skilled in the art may determine if a particularSNP is in LD with an interrogated SNP. The parameter r² is commonly usedin the genetics art to characterize the extent of linkage disequilibriumbetween markers (Hudson, 2001). As used herein, the term “in LD with”refers to a particular SNP that is measured at above the threshold of aparameter such as r² with an interrogated SNP.

It is now common place to directly observe genetic variants in a sampleof chromosomes obtained from a population. Suppose one has genotype dataat two genetic markers located on the same chromosome, for the markers Aand B. Further suppose that two alleles segregate at each of these twomarkers such that alleles A₁ and A₂ can be found at marker A and allelesB₁ and B₂ at marker B. Also assume that these two markers are on a humanautosome. If one is to examine a specific individual and find that theyare heterozygous at both markers, such that their two-marker genotype isA₁A₂B₁B₂, then there are two possible configurations: the individual inquestion could have the alleles A₁B₁ on one chromosome and A₂B₂ on theremaining chromosome; alternatively, the individual could have allelesA₁B₂ on one chromosome and A₂B₁ on the other. The arrangement of alleleson a chromosome is called a haplotype. In this illustration, theindividual could have haplotypes A₁B₁/A₂B₂ or A₁B₂/A₂B₁ (see Hartl andClark (1989) for a more complete description). The concept of linkageequilibrium relates the frequency of haplotypes to the allelefrequencies.

Assume that a sample of individuals is selected from a largerpopulation. Considering the two markers described above, each having twoalleles, there are four possible haplotypes: A₁B₁, A₁B₂, A₂B₁ and A₂B₂.Denote the frequencies of these four haplotypes with the followingnotation.

P ₁₁=freq(A ₁ B ₁)  (1)

P ₁₂=freq(A ₁ B ₂)  (2)

P ₂₁=freq(A ₂ B ₁)  (3)

P ₂₂=freq(A ₂ B ₂)  (4)

The allele frequencies at the two markers are then the sum of differenthaplotype frequencies, it is straightforward to write down a similar setof equations relating single-marker allele frequencies to two-markerhaplotype frequencies:

p ₁₁=freq(A ₁)=P ₁₁ +P ₁₂  (5)

p ₂=freq(A ₂)=P ₂₁ +P ₂₂  (6)

q ₁=freq(B ₁)=P ₁₁ +P ₂₁  (7)

q ₂=freq(B ₂)=P ₁₂ +P ₂₂  (8)

Note that the four haplotype frequencies and the allele frequencies ateach marker must sum to a frequency of 1.

P ₁₁ +P ₁₂ +P ₂₁ +P ₂₂=1  (9)

p ₁ +p ₂=1  (10)

q ₁ +q ₂=1  (11)

If there is no correlation between the alleles at the two markers, onewould expect that the frequency of the haplotypes would be approximatelythe product of the composite alleles. Therefore,

P ₁₁ ≈p ₁ q ₁  (12)

P ₁₂ ≈p ₁ q ₂  (13)

P ₂₁ ≈p ₂ q ₁  (14)

P ₂₂ ≈p ₂ q ₂  (15)

These approximating equations (12)-(15) represent the concept of linkageequilibrium where there is independent assortment between the twomarkers—the alleles at the two markers occur together at random. Theseare represented as approximations because linkage equilibrium andlinkage disequilibrium are concepts typically thought of as propertiesof a sample of chromosomes; and as such they are susceptible tostochastic fluctuations due to the sampling process. Empirically, manypairs of genetic markers will be in linkage equilibrium, but certainlynot all pairs.

Having established the concept of linkage equilibrium above, applicantscan now describe the concept of linkage disequilibrium (LD), which isthe deviation from linkage equilibrium. Since the frequency of the A₁B₁haplotype is approximately the product of the allele frequencies for A₁and B₁ under the assumption of linkage equilibrium as statedmathematically in (12), a simple measure for the amount of departurefrom linkage equilibrium is the difference in these two quantities, D,

D=P ₁₁ −p ₁ q ₁  (16)

D=0 indicates perfect linkage equilibrium. Substantial departures fromD=0 indicates LD in the sample of chromosomes examined. Many propertiesof D are discussed in Lewontin (1964) including the maximum and minimumvalues that D can take. Mathematically, using basic algebra, it can beshown that D can also be written solely in terms of haplotypes:

D=P ₁₁ P ₂₂ −P ₂ P ₂₁  (17)

If one transforms D by squaring it and subsequently dividing by theproduct of the allele frequencies of A₁, A₂, B₁ and B₂, the resultingquantity, called r², is equivalent to the square of the Pearson'scorrelation coefficient commonly used in statistics (e.g., Hoel, 1954).

$\begin{matrix}{r^{2} = \frac{D^{2}}{p_{1}p_{2}q_{1}q_{2}}} & (18)\end{matrix}$

As with D, values of r² close to 0 indicate linkage equilibrium betweenthe two markers examined in the sample set. As values of r² increase,the two markers are said to be in linkage disequilibrium. The range ofvalues that r² can take are from 0 to 1. r²=1 when there is a perfectcorrelation between the alleles at the two markers.

In addition, the quantities discussed above are sample-specific. And assuch, it is necessary to formulate notation specific to the samplesstudied. In the approach discussed here, three types of samples are ofprimary interest: (i) a sample of chromosomes from individuals affectedby a disease-related phenotype (cases), (ii) a sample of chromosomesobtained from individuals not affected by the disease-related phenotype(controls), and (iii) a standard sample set used for the construction ofhaplotypes and calculation pairwise linkage disequilibrium. For theallele frequencies used in the development of the method describedbelow, an additional subscript will be added to denote either the caseor control sample sets.

p _(1,cs)=freq(A ₁ in cases)  (19)

p _(2,cs)=freq(A ₂ in cases)  (20)

q _(1,cs)=freq(B ₁ in cases)  (21)

q _(2,cs)=freq(B ₂ in cases)  (22)

Similarly,

p _(1,ct)=freq(A ₁ in controls)  (23)

p _(2,ct)=freq(A ₂ in controls)  (24)

q _(1,ct)=freq(B ₁ in controls)  (25)

q _(2,ct)=freq(B ₂ in controls)  (26)

As a well-accepted sample set is necessary for robust linkagedisequilibrium calculations, data obtained from the International HapMapproject (The International HapMap Consortium 2003, 2005; Thorisson etal, 2005; McVean et al, 2005) can be used for the calculation ofpairwise r² values. Indeed, the samples genotyped for the InternationalHapMap Project were selected to be representative examples from varioushuman sub-populations with sufficient numbers of chromosomes examined todraw meaningful and robust conclusions from the patterns of geneticvariation observed. The International HapMap project website(hapmap.org) contains a description of the project, methods utilized andsamples examined. It is useful to examine empirical data to get a senseof the patterns present in such data.

Haplotype frequencies were explicit arguments in equation (18) above.However, knowing the 2-marker haplotype frequencies requires that phaseto be determined for doubly heterozygous samples. When phase is unknownin the data examined, various algorithms can be used to infer phase fromthe genotype data. This issue was discussed earlier where the doublyheterozygous individual with a 2-SNP genotype of A₁A₂B₁B₂ could have oneof two different sets of chromosomes: A₁B₁/A₂B₂ or A₁B₂/A₂B₁. One suchalgorithm to estimate haplotype frequencies is theexpectation-maximization (EM) algorithm first formalized by Dempster etal. (1977). This algorithm is often used in genetics to infer haplotypefrequencies from genotype data (e.g. Excoffier and Slatkin (1995);Tregouet et al. (2004)). It should be noted that for the two-SNP caseexplored here, EM algorithms have very little error provided that theallele frequencies and sample sizes are not too small. The impact on r²values is typically negligible.

As correlated genetic markers share information, interrogation of SNPmarkers in LD with a disease-associated SNP marker can also havesufficient power to detect disease association (Long and Langley(1999)). The relationship between the power to directly finddisease-associated alleles and the power to indirectly detectdisease-association was investigated by Pritchard and Przeworski (2001).In a straight-forward derivation, it can be shown that the power todetect disease association indirectly at a marker locus in linkagedisequilibrium with a disease-association locus is approximately thesame as the power to detect disease-association directly at thedisease-association locus if the sample size is increased by a factor of

$\frac{1}{r^{2}}$

(the reciprocal of equation 18) at the marker in comparison with thedisease-association locus.

Therefore, if one calculated the power to detect disease-associationindirectly with an experiment having N samples, then equivalent power todirectly detect disease-association (at the actualdisease-susceptibility locus) would necessitate an experiment usingapproximately r²N samples. This elementary relationship between power,sample size and linkage disequilibrium can be used to derive an r²threshold value useful in determining whether or not genotyping markersin linkage disequilibrium with a SNP marker directly associated withdisease status has enough power to indirectly detectdisease-association.

To commence a derivation of the power to detect disease-associatedmarkers through an indirect process, define the effective chromosomalsample size as

$\begin{matrix}{{n = \frac{4N_{cs}T_{ct}}{N_{cs} + N_{ct}}};} & (27)\end{matrix}$

where N_(ct) and N_(ct) are the numbers of diploid cases and controls,respectively. This is necessary to handle situations where the numbersof cases and controls are not equivalent. For equal case and controlsample sizes, N_(cs)=N_(ct)=N, the value of the effective number ofchromosomes is simply n=2N—as expected. Let power be calculated for asignificance level a (such that traditional P-values below α will bedeemed statistically significant). Define the standard Gaussiandistribution function as Φ(•). Mathematically,

$\begin{matrix}{{\Phi (x)} = {\frac{1}{\sqrt{2\pi}}{\overset{\infty}{\int\limits_{- \infty}}{e^{- \frac{\theta^{2}}{2}}d\; \theta}}}} & (28)\end{matrix}$

Alternatively, the following error function notation (Erf) may also beused,

$\begin{matrix}{{\Phi (x)} = {\frac{1}{2}\lbrack {1 + {{Erf}( \frac{x}{\sqrt{2}} )}} \rbrack}} & (29)\end{matrix}$

For example, Φ(1.644854)=0.95. The value of r² may be derived to yield apre-specified minimum amount of power to detect disease associationthough indirect interrogation. Noting that the LD SNP marker could bethe one that is carrying the disease-association allele, therefore thatthis approach constitutes a lower-bound model where all indirect powerresults are expected to be at least as large as those interrogated.

Denote by β the error rate for not detecting truly disease-associatedmarkers. Therefore, 1−β, is the classical definition of statisticalpower. Substituting the Pritchard-Pzreworski result into the samplesize, the power to detect disease association at a significance level ofa is given by the approximation

$\begin{matrix}{{{1 - \beta} \cong {\Phi\lbrack {\frac{{q_{1,{cs}} - q_{1,{ct}}}}{\sqrt{\frac{{q_{1,{cs}}( {1 - q_{1,{cs}}} )} + {q_{1,{ct}}( {1 - q_{1,{ct}}} )}}{r^{2}n}}} - Z_{1 - \frac{\alpha}{2}}} \rbrack}};} & (30)\end{matrix}$

where Z_(u) is the inverse of the standard normal cumulativedistribution evaluated at u (u∈(0,1)). Z_(u)=Φ⁻¹(u), whereΦ(Φ⁻¹(u))=Φ⁻¹((u))=u. For example, setting α=0.05, and therefore1−α/s=0.975, one obtains Z_(0.975)=1.95996. Next, setting power equal toa threshold of a minimum power of T,

$\begin{matrix}{T = {\Phi\lbrack {\frac{{q_{1,{cs}} - q_{1,{ct}}}}{\sqrt{\frac{{q_{1,{cs}}( {1 - q_{1,{cs}}} )} + {q_{1,{ct}}( {1 - q_{1,{ct}}} )}}{r^{2}n}}} - Z_{1 - \frac{\alpha}{2}}} \rbrack}} & (31)\end{matrix}$

and solving for r², the following threshold r² is obtained:

$\begin{matrix}{r_{T}^{2} = {\frac{\lfloor {{q_{1,{cs}}( {1 - q_{1,{cs}}} )} + {q_{1,{ct}}( {1 - q_{1,{ct}}} )}} \rfloor}{{n( {q_{1,{cs}} - q_{1,{ct}}} )}^{2}}\lbrack {{\Phi^{- 1}(T)} + Z_{1 - \frac{\alpha}{2}}} \rbrack}^{2}} & (32) \\{{Or},} & \; \\{r_{T}^{2} = {\frac{( {Z_{T} + Z_{1 - \frac{\alpha}{2}}} )^{2}}{n}\lbrack \frac{q_{1,{cs}} - ( q_{1,{cs}} )^{2} + q_{1,{ct}} - ( q_{1,{ct}} )^{2}}{( {q_{1,{cs}} - q_{1,{ct}}} )^{2}} \rbrack}} & (33)\end{matrix}$

Suppose that r² is calculated between an interrogated SNP and a numberof other SNPs with varying levels of LD with the interrogated SNP. Thethreshold value r_(T) ² is the minimum value of linkage disequilibriumbetween the interrogated SNP and the potential LD SNPs such that the LDSNP still retains a power greater or equal to T for detectingdisease-association. For example, suppose that SNP rs200 is genotyped ina case-control disease-association study and it is found to beassociated with a disease phenotype. Further suppose that the minorallele frequency in 1,000 case chromosomes was found to be 16% incontrast with a minor allele frequency of 10% in 1,000 controlchromosomes. Given those measurements one could have predicted, prior tothe experiment, that the power to detect disease association at asignificance level of 0.05 was quite high—approximately 98% using a testof allelic association. Applying equation (32) one can calculate aminimum value of r² to indirectly assess disease association assumingthat the minor allele at SNP rs200 is truly disease-predisposing for athreshold level of power. If one sets the threshold level of power to be80%, then r_(T) ²=0.489 given the same significance level and chromosomenumbers as above. Hence, any SNP with a pairwise r² value with rs200greater than 0.489 is expected to have greater than 80% power to detectthe disease association. Further, this is assuming the conservativemodel where the LD SNP is disease-associated only through linkagedisequilibrium with the interrogated SNP rs200.

Imputation

Genotypes of SNPs can be imputed without actually having to be directlygenotyped (referred to as “imputation”), by using known haplotypeinformation. Imputation is a process to provide “missing” data, eithermissing individual genotypes or missing SNPs and concomitant genotypes,which have not been directly genotyped (i.e., assayed). Imputation isparticularly useful for identifying disease associations for specificungenotyped SNPs by inferring the missing genotypes to these ungenotypedSNPs. Although the process uses similar information to LD, since thephasing and imputation process uses information from multiple SNPs atthe same time, the phased haplotype, it is able to infer the genotypeand achieve high identifiable accuracy. Genotype information (such asfrom the HapMap project by The International HapMap Consortium) can beused to infer haplotype phase and impute genotypes for SNPs that are notdirectly genotyped in a given individual or sample set (such as for adisease association study). In general, imputation uses a referencedataset in which the genotypes of potential SNPs that are to be testedfor disease association have been determined in multiple individuals(such as in HapMap); the individuals in the reference dataset are thenhaplotype phased. This phasing can be done with independent programssuch as fastPHASE (Sheet and Stephens, Am J Hum Genet (2006) 76:629-644) or a combination program such as BEAGLE which does both thephasing and the imputation. The reference phased haplotypes and processcan be checked using the children of the HapMap individual parents,among other mechanisms. Once the reference phased haplotypes have beencreated, the imputation of additional individuals for SNPs genotyped orcomplete sets of SNPs that have not been directly genotyped can thenproceed. The HapMap dataset is particularly useful as the referencedataset, however other datasets can be used. Since the imputationcreates new concommitant phased haplotypes for individuals in theassociation study and these contain other SNPs within the genomicregion, these ungenotyped but imputed SNPs can also be tested fordisease assocations (or other traits). Certain exemplary methods forhaplotype phase inference and imputation of missing genotypes utilizethe BEAGLE genetic analysis program, (Browning, Hum Genet (2008)124:439-450).

Thus, SNPs for which genotypes are imputed can be tested for associationwith a disease or other trait even though these SNPs are not directlygenotyped. The SNPs for which genotypes are imputed have genotype dataavailable in the reference dataset, e.g. HapMap individuals, but theyare not directly genotyped in a particular individual or sample set(such as in a particular disease association study).

In addition to using a reference dataset (e.g., HapMap) to imputegenotypes of SNPs that are not directly genotyped in a study, imputationcan provide genotypes of SNPs that were directly genotyped in a studybut for which the genotypes are missing, in some or most of theindividuals, for some reason, such as because they failed to passquality control. Imputation can also be used to combine genotypingresults from multiple studies in which different sets of SNPs weregenotyped to construct a complete meta-analysis. For example, genotypedand imputed genotyped SNP results from multiple different studies can becombined, and the overlapping SNP genotypes (e.g., genotyped in onestudy, imputed in another study or imputed in both or genotyped in both)can be analyzed across all of the studies (Browning, Hum Genet (2008)124:439-450).

For a review of imputation (as well as the BEAGLE program), seeBrowning, “Missing data imputation and haplotype phase inference forgenome-wide association studies”, Hum Genet (2008) 124:439-450 andBrowning et al. “A unified approach to genotype imputation andhaplotype-phase inference for large data sets of trios and unrelatedindividuals”, Am J Hum Genet. (2009) February; 84(2):210-23, each ofwhich is incorporated herein by reference in its entirety.

The contribution or association of particular SNPs with statin responseor disease phenotypes, such as VT, enables the SNPs of the presentinvention to be used to develop superior diagnostic tests capable ofidentifying individuals who express a detectable trait, such as reducedrisk for VT in response to statin treatment, as the result of a specificgenotype, or individuals whose genotype places them at an increased ordecreased risk of developing a detectable trait at a subsequent time ascompared to individuals who do not have that genotype. As describedherein, diagnostics may be based on a single SNP or a group of SNPs.Combined detection of a plurality of SNPs (for example, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 30, 32, 48,50, 64, 96, 100, or any other number in-between, or more, of the SNPsprovided in Table 1 and/or Table 2) typically increases the probabilityof an accurate diagnosis. For example, the presence of a single SNPknown to correlate with VT might indicate a probability of 20% that anindividual has or is at risk of developing VT, whereas detection of fiveSNPs, each of which correlates with VT, might indicate a probability of80% that an individual has or is at risk of developing VT. To furtherincrease the accuracy of diagnosis or predisposition screening, analysisof the SNPs of the present invention can be combined with that of otherpolymorphisms or other risk factors of VT, such as disease symptoms,pathological characteristics, family history, diet, environmentalfactors, or lifestyle factors.

It will be understood by practitioners skilled in the treatment ordiagnosis of VT that the present invention generally does not intend toprovide an absolute identification of individuals who benefit fromstatin treatment or individuals who are at risk (or less at risk) ofdeveloping VT, but rather to indicate a certain increased (or decreased)degree or likelihood of responding to statin therapy or developing VTbased on statistically significant association results. However, thisinformation is extremely valuable as it can be used to, for example,encourage individuals to comply with their statin regimens as prescribedby their doctors (even though the benefit of maintaining statin therapymay not be overtly apparent, which often leads to lack of compliancewith prescribed statin treatment), to initiate preventive treatments orto allow an individual carrying one or more significant SNPs or SNPhaplotypes to foresee warning signs such as minor clinical symptoms, orto have regularly scheduled physical exams to monitor for appearance ofa condition in order to identify and begin treatment of the condition atan early stage. Particularly with diseases that are extremelydebilitating or fatal if not treated on time, the knowledge of apotential predisposition, even if this predisposition is not absolute,would likely contribute in a very significant manner to treatmentefficacy.

The diagnostic techniques of the present invention may employ a varietyof methodologies to determine whether a test subject has a SNP orcombination of SNPs associated with an increased or decreased risk ofdeveloping a detectable trait or whether the individual suffers from adetectable trait as a result of a particular polymorphism/mutation,including, for example, methods which enable the analysis of individualchromosomes for haplotyping, family studies, single sperm DNA analysis,or somatic hybrids. The trait analyzed using the diagnostics of theinvention may be any detectable trait that is commonly observed inpathologies and disorders related to VT or drug response.

Another aspect of the present invention relates to a method ofdetermining whether an individual is at risk (or less at risk) ofdeveloping one or more traits or whether an individual expresses one ormore traits as a consequence of possessing a particular trait-causing ortrait-influencing allele. These methods generally involve obtaining anucleic acid sample from an individual and assaying the nucleic acidsample to determine which nucleotide(s) is/are present at one or moreSNP positions, wherein the assayed nucleotide(s) is/are indicative of anincreased or decreased risk of developing the trait or indicative thatthe individual expresses the trait as a result of possessing aparticular trait-causing or trait-influencing allele.

In another embodiment, the SNP detection reagents of the presentinvention are used to determine whether an individual has one or moreSNP allele(s) affecting the level (e.g., the concentration of mRNA orprotein in a sample, etc.) or pattern (e.g., the kinetics of expression,rate of decomposition, stability profile, Km, Vmax, etc.) of geneexpression (collectively, the “gene response” of a cell or bodilyfluid). Such a determination can be accomplished by screening for mRNAor protein expression (e.g., by using nucleic acid arrays, RT-PCR,TaqMan assays, or mass spectrometry), identifying genes having alteredexpression in an individual, genotyping SNPs disclosed in Table 1 and/orTable 2 that could affect the expression of the genes having alteredexpression (e.g., SNPs that are in and/or around the gene(s) havingaltered expression, SNPs in regulatory/control regions, SNPs in and/oraround other genes that are involved in pathways that could affect theexpression of the gene(s) having altered expression, or all SNPs couldbe genotyped), and correlating SNP genotypes with altered geneexpression. In this manner, specific SNP alleles at particular SNP sitescan be identified that affect gene expression.

Therapeutics, Pharmacogenomics, and Drug Development

Therapeutic Methods and Compositions

In certain aspects of the invention, there are provided methods ofassaying (i.e., testing) one or more SNPs provided by the presentinvention in an individual's nucleic acids, and administering atherapeutic or preventive agent to the individual based on the allele(s)present at the SNP(s) having indicated that the individual can benefitfrom the therapeutic or preventive agent.

In further aspects of the invention, there are provided methods ofassaying one or more SNPs provided by the present invention in anindividual's nucleic acids, and administering a diagnostic agent (e.g.,an imaging agent), or otherwise carrying out further diagnosticprocedures on the individual, based on the allele(s) present at theSNP(s) having indicated that the diagnostic agents or diagnosticsprocedures are justified in the individual.

In yet other aspects of the invention, there is provided apharmaceutical pack comprising a therapeutic agent (e.g., a smallmolecule drug, antibody, peptide, antisense or RNAi nucleic acidmolecule, etc.) and a set of instructions for administration of thetherapeutic agent to an individual who has been tested for one or moreSNPs provided by the present invention.

Pharmacogenomics

The present invention provides methods for assessing thepharmacogenomics of a subject harboring particular SNP alleles orhaplotypes to a particular therapeutic agent or pharmaceutical compound,or to a class of such compounds. Pharmacogenomics deals with the roleswhich clinically significant hereditary variations (e.g., SNPs) play inthe response to drugs due to altered drug disposition and/or abnormalaction in affected persons. See, e.g., Roses, Nature 405, 857-865(2000); Gould Rothberg, Nature Biotechnology 19, 209-211 (2001);Eichelbaum, Clin Exp Pharmacol Physiol 23(10-11):983-985 (1996); andLinder, Clin Chem 43(2):254-266 (1997). The clinical outcomes of thesevariations can result in severe toxicity of therapeutic drugs in certainindividuals or therapeutic failure of drugs in certain individuals as aresult of individual variation in metabolism. Thus, the SNP genotype ofan individual can determine the way a therapeutic compound acts on thebody or the way the body metabolizes the compound. For example, SNPs indrug metabolizing enzymes can affect the activity of these enzymes,which in turn can affect both the intensity and duration of drug action,as well as drug metabolism and clearance.

The discovery of SNPs in drug metabolizing enzymes, drug transporters,proteins for pharmaceutical agents, and other drug targets has explainedwhy some patients do not obtain the expected drug effects, show anexaggerated drug effect, or experience serious toxicity from standarddrug dosages. SNPs can be expressed in the phenotype of the extensivemetabolizer and in the phenotype of the poor metabolizer. Accordingly,SNPs may lead to allelic variants of a protein in which one or more ofthe protein functions in one population are different from those inanother population. SNPs and the encoded variant peptides thus providetargets to ascertain a genetic predisposition that can affect treatmentmodality. For example, in a ligand-based treatment, SNPs may give riseto amino terminal extracellular domains and/or other ligand-bindingregions of a receptor that are more or less active in ligand binding,thereby affecting subsequent protein activation. Accordingly, liganddosage would necessarily be modified to maximize the therapeutic effectwithin a given population containing particular SNP alleles orhaplotypes.

As an alternative to genotyping, specific variant proteins containingvariant amino acid sequences encoded by alternative SNP alleles could beidentified. Thus, pharmacogenomic characterization of an individualpermits the selection of effective compounds and effective dosages ofsuch compounds for prophylactic or therapeutic uses based on theindividual's SNP genotype, thereby enhancing and optimizing theeffectiveness of the therapy. Furthermore, the production of recombinantcells and transgenic animals containing particular SNPs/haplotypes alloweffective clinical design and testing of treatment compounds and dosageregimens. For example, transgenic animals can be produced that differonly in specific SNP alleles in a gene that is orthologous to a humandisease susceptibility gene.

Pharmacogenomic uses of the SNPs of the present invention provideseveral significant advantages for patient care, particularly inpredicting an individual's responsiveness to statin treatment(particularly for reducing the risk of VT) and in predicting anindividual's predisposition to VT. Pharmacogenomic characterization ofan individual, based on an individual's SNP genotype, can identify thoseindividuals unlikely to respond to treatment with a particularmedication and thereby allows physicians to avoid prescribing theineffective medication to those individuals. On the other hand, SNPgenotyping of an individual may enable physicians to select theappropriate medication and dosage regimen that will be most effectivebased on an individual's SNP genotype. This information increases aphysician's confidence in prescribing medications and motivates patientsto comply with their drug regimens. Furthermore, pharmacogenomics mayidentify patients predisposed to toxicity and adverse reactions toparticular drugs or drug dosages. Adverse drug reactions lead to morethan 100,000 avoidable deaths per year in the United States alone andtherefore represent a significant cause of hospitalization and death, aswell as a significant economic burden on the healthcare system (Pfost etal., Trends in Biotechnology, August 2000.). Thus, pharmacogenomicsbased on the SNPs disclosed herein has the potential to both save livesand reduce healthcare costs substantially.

Pharmacogenomics in general is discussed further in Rose et al.,“Pharmacogenetic analysis of clinically relevant genetic polymorphisms,”Methods Mol Med 85:225-37 (2003). Pharmacogenomics as it relates toAlzheimer's disease and other neurodegenerative disorders is discussedin Cacabelos, “Pharmacogenomics for the treatment of dementia,” Ann Med34(5):357-79 (2002); Maimone et al., “Pharmacogenomics ofneurodegenerative diseases,” Eur J Pharmacol 413(1):11-29 (February2001); and Poirier, “Apolipoprotein E: a pharmacogenetic target for thetreatment of Alzheimer's disease,” Mol Diagn 4(4):335-41 (December1999). Pharmacogenomics as it relates to cardiovascular disorders isdiscussed in Siest et al., “Pharmacogenomics of drugs affecting thecardiovascular system,” Clin Chem Lab Med 41(4):590-9 (April 2003);Mukherjee et al., “Pharmacogenomics in cardiovascular diseases,” ProgCardiovasc Dis 44(6):479-98 (May-June 2002); and Mooser et al.,“Cardiovascular pharmacogenetics in the SNP era,” J Thromb Haemost1(7):1398-402 (July 2003). Pharmacogenomics as it relates to cancer isdiscussed in McLeod et al., “Cancer pharmacogenomics: SNPs, chips, andthe individual patient,” Cancer Invest 21(4):630-40 (2003); and Watterset al., “Cancer pharmacogenomics: current and future applications,”Biochim Biophys Acta 1603(2):99-111 (March 2003).

Clinical Trials

In certain aspects of the invention, there are provided methods of usingthe SNPs disclosed herein to identify or stratify patient populationsfor clinical trials of a therapeutic, preventive, or diagnostic agent.

For instance, an aspect of the present invention includes selectingindividuals for clinical trials based on their SNP genotype, such asselecting individuals for inclusion in a clinical trial and/or assigningindividuals to a particular group within a clinical trial (e.g., an“arm” or “cohort” of the trial). For example, individuals with SNPgenotypes that indicate that they are likely to positively respond to adrug can be included in the trials, whereas those individuals whose SNPgenotypes indicate that they are less likely to or would not respond tothe drug, or who are at risk for suffering toxic effects or otheradverse reactions, can be excluded from the clinical trials. This notonly can improve the safety of clinical trials, but also can enhance thechances that the trial will demonstrate statistically significantefficacy. Further, one can stratify a prospective trial with patientswith different SNP variants to determine the impact of differential drugtreatment.

Thus, certain embodiments of the invention provide methods forconducting a clinical trial of a therapeutic agent in which a human isselected for inclusion in the clinical trial and/or assigned to aparticular group within a clinical trial based on the presence orabsence of one or more SNPs disclosed herein. In certain embodiments,the therapeutic agent is a statin.

In certain exemplary embodiments, SNPs of the invention can be used toselect individuals who are unlikely to respond positively to aparticular therapeutic agent (or class of therapeutic agents) based ontheir SNP genotype(s) to participate in a clinical trial of another typeof drug that may benefit them. Thus, in certain embodiments, the SNPs ofthe invention can be used to identify patient populations who do notadequately respond to current treatments and are therefore in need ofnew therapies. This not only benefits the patients themselves, but alsobenefits organizations such as pharmaceutical companies by enabling theidentification of populations that represent markets for new drugs, andenables the efficacy of these new drugs to be tested during clinicaltrials directly in individuals within these markets.

The SNP-containing nucleic acid molecules of the present invention arealso useful for monitoring the effectiveness of modulating compounds onthe expression or activity of a variant gene, or encoded product,particularly in a treatment regimen or in clinical trials. Thus, thegene expression pattern can serve as an indicator for the continuingeffectiveness of treatment with the compound, particularly withcompounds to which a patient can develop resistance, as well as anindicator for toxicities. The gene expression pattern can also serve asa marker indicative of a physiological response of the affected cells tothe compound. Accordingly, such monitoring would allow either increasedadministration of the compound or the administration of alternativecompounds to which the patient has not become resistant.

Furthermore, the SNPs of the present invention may have utility indetermining why certain previously developed drugs performed poorly inclinical trials and may help identify a subset of the population thatwould benefit from a drug that had previously performed poorly inclinical trials, thereby “rescuing” previously developed drugs, andenabling the drug to be made available to a particular patientpopulation (e.g., particular VT patients) that can benefit from it.

Identification, Screening, and Use of Therapeutic Agents

The SNPs of the present invention also can be used to identify noveltherapeutic targets for VT. For example, genes containing thedisease-associated variants (“variant genes”) or their products, as wellas genes or their products that are directly or indirectly regulated byor interacting with these variant genes or their products, can betargeted for the development of therapeutics that, for example, treatthe disease or prevent or delay disease onset. The therapeutics may becomposed of, for example, small molecules, proteins, protein fragmentsor peptides, antibodies, nucleic acids, or their derivatives or mimeticswhich modulate the functions or levels of the target genes or geneproducts.

The invention further provides methods for identifying a compound oragent that can be used to treat VT. The SNPs disclosed herein are usefulas targets for the identification and/or development of therapeuticagents. A method for identifying a therapeutic agent or compoundtypically includes assaying the ability of the agent or compound tomodulate the activity and/or expression of a SNP-containing nucleic acidor the encoded product and thus identifying an agent or a compound thatcan be used to treat a disorder characterized by undesired activity orexpression of the SNP-containing nucleic acid or the encoded product.The assays can be performed in cell-based and cell-free systems.Cell-based assays can include cells naturally expressing the nucleicacid molecules of interest or recombinant cells genetically engineeredto express certain nucleic acid molecules.

Variant gene expression in a VT patient can include, for example, eitherexpression of a SNP-containing nucleic acid sequence (for instance, agene that contains a SNP can be transcribed into an mRNA transcriptmolecule containing the SNP, which can in turn be translated into avariant protein) or altered expression of a normal/wild-type nucleicacid sequence due to one or more SNPs (for instance, aregulatory/control region can contain a SNP that affects the level orpattern of expression of a normal transcript).

Assays for variant gene expression can involve direct assays of nucleicacid levels (e.g., mRNA levels), expressed protein levels, or ofcollateral compounds involved in a signal pathway. Further, theexpression of genes that are up- or down-regulated in response to thesignal pathway can also be assayed. In this embodiment, the regulatoryregions of these genes can be operably linked to a reporter gene such asluciferase.

Modulators of variant gene expression can be identified in a methodwherein, for example, a cell is contacted with a candidatecompound/agent and the expression of mRNA determined. The level ofexpression of mRNA in the presence of the candidate compound is comparedto the level of expression of mRNA in the absence of the candidatecompound. The candidate compound can then be identified as a modulatorof variant gene expression based on this comparison and be used to treata disorder such as VT that is characterized by variant gene expression(e.g., either expression of a SNP-containing nucleic acid or alteredexpression of a normal/wild-type nucleic acid molecule due to one ormore SNPs that affect expression of the nucleic acid molecule) due toone or more SNPs of the present invention. When expression of mRNA isstatistically significantly greater in the presence of the candidatecompound than in its absence, the candidate compound is identified as astimulator of nucleic acid expression. When nucleic acid expression isstatistically significantly less in the presence of the candidatecompound than in its absence, the candidate compound is identified as aninhibitor of nucleic acid expression.

The invention further provides methods of treatment, with the SNP orassociated nucleic acid domain (e.g., catalytic domain,ligand/substrate-binding domain, regulatory/control region, etc.) orgene, or the encoded mRNA transcript, as a target, using a compoundidentified through drug screening as a gene modulator to modulatevariant nucleic acid expression. Modulation can include eitherup-regulation (i.e., activation or agonization) or down-regulation(i.e., suppression or antagonization) of nucleic acid expression.

Expression of mRNA transcripts and encoded proteins, either wild type orvariant, may be altered in individuals with a particular SNP allele in aregulatory/control element, such as a promoter or transcription factorbinding domain, that regulates expression. In this situation, methods oftreatment and compounds can be identified, as discussed herein, thatregulate or overcome the variant regulatory/control element, therebygenerating normal, or healthy, expression levels of either the wild typeor variant protein.

Pharmaceutical Compositions and Administration Thereof

Any of the statin response-associated proteins, and encoding nucleicacid molecules, disclosed herein can be used as therapeutic targets (ordirectly used themselves as therapeutic compounds) for treating orpreventing VT, and the present disclosure enables therapeutic compounds(e.g., small molecules, antibodies, therapeutic proteins, RNAi andantisense molecules, etc.) to be developed that target (or are comprisedof) any of these therapeutic targets.

In general, a therapeutic compound will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. The actualamount of the therapeutic compound of this invention, i.e., the activeingredient, will depend upon numerous factors such as the severity ofthe disease to be treated, the age and relative health of the subject,the potency of the compound used, the route and form of administration,and other factors.

Therapeutically effective amounts of therapeutic compounds may rangefrom, for example, approximately 0.01-50 mg per kilogram body weight ofthe recipient per day; preferably about 0.1-20 mg/kg/day. Thus, as anexample, for administration to a 70-kg person, the dosage range wouldmost preferably be about 7 mg to 1.4 g per day.

In general, therapeutic compounds will be administered as pharmaceuticalcompositions by any one of the following routes: oral, systemic (e.g.,transdermal, intranasal, or by suppository), or parenteral (e.g.,intramuscular, intravenous, or subcutaneous) administration. Thepreferred manner of administration is oral or parenteral using aconvenient daily dosage regimen, which can be adjusted according to thedegree of affliction. Oral compositions can take the form of tablets,pills, capsules, semisolids, powders, sustained release formulations,solutions, suspensions, elixirs, aerosols, or any other appropriatecompositions.

The choice of formulation depends on various factors such as the mode ofdrug administration (e.g., for oral administration, formulations in theform of tablets, pills, or capsules are preferred) and thebioavailability of the drug substance. Recently, pharmaceuticalformulations have been developed especially for drugs that show poorbioavailability based upon the principle that bioavailability can beincreased by increasing the surface area, i.e., decreasing particlesize. For example, U.S. Pat. No. 4,107,288 describes a pharmaceuticalformulation having particles in the size range from 10 to 1,000 nm inwhich the active material is supported on a cross-linked matrix ofmacromolecules. U.S. Pat. No. 5,145,684 describes the production of apharmaceutical formulation in which the drug substance is pulverized tonanoparticles (average particle size of 400 nm) in the presence of asurface modifier and then dispersed in a liquid medium to give apharmaceutical formulation that exhibits remarkably highbioavailability.

Pharmaceutical compositions are comprised of, in general, a therapeuticcompound in combination with at least one pharmaceutically acceptableexcipient. Acceptable excipients are non-toxic, aid administration, anddo not adversely affect the therapeutic benefit of the therapeuticcompound. Such excipients may be any solid, liquid, semi-solid or, inthe case of an aerosol composition, gaseous excipient that is generallyavailable to one skilled in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk and the like. Liquid and semisolid excipientsmay be selected from glycerol, propylene glycol, water, ethanol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesameoil, etc. Preferred liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse a compound of this invention inaerosol form. Inert gases suitable for this purpose are nitrogen, carbondioxide, etc.

Other suitable pharmaceutical excipients and their formulations aredescribed in Remington's Pharmaceutical Sciences 18^(th) ed., E. W.Martin, ed., Mack Publishing Company (1990).

The amount of the therapeutic compound in a formulation can vary withinthe full range employed by those skilled in the art. Typically, theformulation will contain, on a weight percent (wt %) basis, from about0.01-99.99 wt % of the therapeutic compound based on the totalformulation, with the balance being one or more suitable pharmaceuticalexcipients. Preferably, the compound is present at a level of about1-80% wt.

Therapeutic compounds can be administered alone or in combination withother therapeutic compounds or in combination with one or more otheractive ingredient(s). For example, an inhibitor or stimulator of aVT-associated protein can be administered in combination with anotheragent that inhibits or stimulates the activity of the same or adifferent VT-associated protein to thereby counteract the effects of VT.

For further information regarding pharmacology, see Current Protocols inPharmacology, John Wiley & Sons, Inc., N.Y.

Nucleic Acid-Based Therapeutic Agents

The SNP-containing nucleic acid molecules disclosed herein, and theircomplementary nucleic acid molecules, may be used as antisenseconstructs to control gene expression in cells, tissues, and organisms.Antisense technology is well established in the art and extensivelyreviewed in Antisense Drug Technology: Principles, Strategies, andApplications, Crooke, ed., Marcel Dekker, Inc., N.Y. (2001). Anantisense nucleic acid molecule is generally designed to becomplementary to a region of mRNA expressed by a gene so that theantisense molecule hybridizes to the mRNA and thereby blocks translationof mRNA into protein. Various classes of antisense oligonucleotides areused in the art, two of which are cleavers and blockers. Cleavers, bybinding to target RNAs, activate intracellular nucleases (e.g., RNaseHor RNase L) that cleave the target RNA. Blockers, which also bind totarget RNAs, inhibit protein translation through steric hindrance ofribosomes. Exemplary blockers include peptide nucleic acids,morpholinos, locked nucleic acids, and methylphosphonates. See, e.g.,Thompson, Drug Discovery Today 7(17): 912-917 (2002). Antisenseoligonucleotides are directly useful as therapeutic agents, and are alsouseful for determining and validating gene function (e.g., in geneknock-out or knock-down experiments).

Antisense technology is further reviewed in: Lavery et al., “Antisenseand RNAi: powerful tools in drug target discovery and validation,” CurrOpin Drug Discov Devel 6(4):561-9 (July 2003); Stephens et al.,“Antisense oligonucleotide therapy in cancer,” Curr Opin Mol Ther5(2):118-22 (April 2003); Kurreck, “Antisense technologies. Improvementthrough novel chemical modifications,” Eur J Biochem 270(8):1628-44(April 2003); Dias et al., “Antisense oligonucleotides: basic conceptsand mechanisms,” Mol Cancer Ther 1(5):347-55 (March 2002); Chen,“Clinical development of antisense oligonucleotides as anti-cancertherapeutics,” Methods Mol Med 75:621-36 (2003); Wang et al., “Antisenseanticancer oligonucleotide therapeutics,” Curr Cancer Drug Targets1(3):177-96 (November 2001); and Bennett, “Efficiency of antisenseoligonucleotide drug discovery,” Antisense Nucleic Acid Drug Dev12(3):215-24 (June 2002).

The SNPs of the present invention are particularly useful for designingantisense reagents that are specific for particular nucleic acidvariants. Based on the SNP information disclosed herein, antisenseoligonucleotides can be produced that specifically target mRNA moleculesthat contain one or more particular SNP nucleotides. In this manner,expression of mRNA molecules that contain one or more undesiredpolymorphisms (e.g., SNP nucleotides that lead to a defective proteinsuch as an amino acid substitution in a catalytic domain) can beinhibited or completely blocked. Thus, antisense oligonucleotides can beused to specifically bind a particular polymorphic form (e.g., a SNPallele that encodes a defective protein), thereby inhibiting translationof this form, but which do not bind an alternative polymorphic form(e.g., an alternative SNP nucleotide that encodes a protein havingnormal function).

Antisense molecules can be used to inactivate mRNA in order to inhibitgene expression and production of defective proteins. Accordingly, thesemolecules can be used to treat a disorder, such as VT, characterized byabnormal or undesired gene expression or expression of certain defectiveproteins. This technique can involve cleavage by means of ribozymescontaining nucleotide sequences complementary to one or more regions inthe mRNA that attenuate the ability of the mRNA to be translated.Possible mRNA regions include, for example, protein-coding regions andparticularly protein-coding regions corresponding to catalyticactivities, substrate/ligand binding, or other functional activities ofa protein.

The SNPs of the present invention are also useful for designing RNAinterference reagents that specifically target nucleic acid moleculeshaving particular SNP variants. RNA interference (RNAi), also referredto as gene silencing, is based on using double-stranded RNA (dsRNA)molecules to turn genes off. When introduced into a cell, dsRNAs areprocessed by the cell into short fragments (generally about 21, 22, or23 nucleotides in length) known as small interfering RNAs (siRNAs) whichthe cell uses in a sequence-specific manner to recognize and destroycomplementary RNAs. Thompson, Drug Discovery Today 7(17): 912-917(2002). Accordingly, an aspect of the present invention specificallycontemplates isolated nucleic acid molecules that are about 18-26nucleotides in length, preferably 19-25 nucleotides in length, and morepreferably 20, 21, 22, or 23 nucleotides in length, and the use of thesenucleic acid molecules for RNAi. Because RNAi molecules, includingsiRNAs, act in a sequence-specific manner, the SNPs of the presentinvention can be used to design RNAi reagents that recognize and destroynucleic acid molecules having specific SNP alleles/nucleotides (such asdeleterious alleles that lead to the production of defective proteins),while not affecting nucleic acid molecules having alternative SNPalleles (such as alleles that encode proteins having normal function).As with antisense reagents, RNAi reagents may be directly useful astherapeutic agents (e.g., for turning off defective, disease-causinggenes), and are also useful for characterizing and validating genefunction (e.g., in gene knock-out or knock-down experiments).

The following references provide a further review of RNAi: Reynolds etal., “Rational siRNA design for RNA interference,” Nat Biotechnol22(3):326-30 (March 2004); Epub Feb. 1, 2004; Chi et al., “Genomewideview of gene silencing by small interfering RNAs,” PNAS100(11):6343-6346 (2003); Vickers et al., “Efficient Reduction of TargetRNAs by Small Interfering RNA and RNase H-dependent Antisense Agents,” JBiol Chem 278:7108-7118 (2003); Agami, “RNAi and related mechanisms andtheir potential use for therapy,” Curr Opin Chem Biol 6(6):829-34(December 2002); Lavery et al., “Antisense and RNAi: powerful tools indrug target discovery and validation,” Curr Opin Drug Discov Devel6(4):561-9 (July 2003); Shi, “Mammalian RNAi for the masses,” TrendsGenet 19(1):9-12 (January 2003); Shuey et al., “RNAi: gene-silencing intherapeutic intervention,” Drug Discovery Today 7(20): 1040-1046(October 2002); McManus et al., Nat Rev Genet 3(10):737-47 (October2002); Xia et al., Nat Biotechnol 20(10):1006-10 (October 2002);Plasterk et al., Curr Opin Genet Dev 10(5):562-7 (October 2000); Bosheret al., Nat Cell Biol 2(2):E31-6 (February 2000); and Hunter, Curr Biol17; 9(12):R440-2 (June 1999).

Other Therapeutic Aspects

SNPs have many important uses in drug discovery, screening, anddevelopment, and thus the SNPs of the present invention are useful forimproving many different aspects of the drug development process.

For example, a high probability exists that, for any gene/proteinselected as a potential drug target, variants of that gene/protein willexist in a patient population. Thus, determining the impact ofgene/protein variants on the selection and delivery of a therapeuticagent should be an integral aspect of the drug discovery and developmentprocess. Jazwinska, A Trends Guide to Genetic Variation and GenomicMedicine S30-S36 (March 2002).

Knowledge of variants (e.g., SNPs and any corresponding amino acidpolymorphisms) of a particular therapeutic target (e.g., a gene, mRNAtranscript, or protein) enables parallel screening of the variants inorder to identify therapeutic candidates (e.g., small moleculecompounds, antibodies, antisense or RNAi nucleic acid compounds, etc.)that demonstrate efficacy across variants. Rothberg, Nat Biotechnol19(3):209-11 (March 2001). Such therapeutic candidates would be expectedto show equal efficacy across a larger segment of the patientpopulation, thereby leading to a larger potential market for thetherapeutic candidate.

Furthermore, identifying variants of a potential therapeutic targetenables the most common form of the target to be used for selection oftherapeutic candidates, thereby helping to ensure that the experimentalactivity that is observed for the selected candidates reflects the realactivity expected in the largest proportion of a patient population.Jazwinska, A Trends Guide to Genetic Variation and Genomic MedicineS30-S36 (March 2002).

Additionally, screening therapeutic candidates against all knownvariants of a target can enable the early identification of potentialtoxicities and adverse reactions relating to particular variants. Forexample, variability in drug absorption, distribution, metabolism andexcretion (ADME) caused by, for example, SNPs in therapeutic targets ordrug metabolizing genes, can be identified, and this information can beutilized during the drug development process to minimize variability indrug disposition and develop therapeutic agents that are safer across awider range of a patient population. The SNPs of the present invention,including the variant proteins and encoding polymorphic nucleic acidmolecules provided in Tables 1 and 2, are useful in conjunction with avariety of toxicology methods established in the art, such as those setforth in Current Protocols in Toxicology, John Wiley & Sons, Inc., N.Y.

Furthermore, therapeutic agents that target any art-known proteins (ornucleic acid molecules, either RNA or DNA) may cross-react with thevariant proteins (or polymorphic nucleic acid molecules) disclosed inTable 1, thereby significantly affecting the pharmacokinetic propertiesof the drug. Consequently, the protein variants and the SNP-containingnucleic acid molecules disclosed in Tables 1 and 2 are useful indeveloping, screening, and evaluating therapeutic agents that targetcorresponding art-known protein forms (or nucleic acid molecules).Additionally, as discussed above, knowledge of all polymorphic forms ofa particular drug target enables the design of therapeutic agents thatare effective against most or all such polymorphic forms of the drugtarget.

A subject suffering from a pathological condition ascribed to a SNP,such as VT, may be treated so as to correct the genetic defect. See Krenet al., Proc Natl Acad Sci USA 96:10349-10354 (1999). Such a subject canbe identified by any method that can detect the polymorphism in abiological sample drawn from the subject. Such a genetic defect may bepermanently corrected by administering to such a subject a nucleic acidfragment incorporating a repair sequence that supplies thenormal/wild-type nucleotide at the position of the SNP. Thissite-specific repair sequence can encompass an RNA/DNA oligonucleotidethat operates to promote endogenous repair of a subject's genomic DNA.The site-specific repair sequence is administered in an appropriatevehicle, such as a complex with polyethylenimine, encapsulated inanionic liposomes, a viral vector such as an adenovirus, or otherpharmaceutical composition that promotes intracellular uptake of theadministered nucleic acid. A genetic defect leading to an inbornpathology may then be overcome, as the chimeric oligonucleotides induceincorporation of the normal sequence into the subject's genome. Uponincorporation, the normal gene product is expressed, and the replacementis propagated, thereby engendering a permanent repair and therapeuticenhancement of the clinical condition of the subject.

In cases in which a cSNP results in a variant protein that is ascribedto be the cause of, or a contributing factor to, a pathologicalcondition, a method of treating such a condition can includeadministering to a subject experiencing the pathology thewild-type/normal cognate of the variant protein. Once administered in aneffective dosing regimen, the wild-type cognate provides complementationor remediation of the pathological condition.

Variant Proteins, Antibodies, Vectors, Host Cells, & Uses Thereof

Variant Proteins Encoded by SNP-Containing Nucleic Acid Molecules

The present invention provides SNP-containing nucleic acid molecules,many of which encode proteins having variant amino acid sequences ascompared to the art-known (i.e., wild-type) proteins. Amino acidsequences encoded by the polymorphic nucleic acid molecules of thepresent invention are referred to as SEQ ID NOS:85-168 in Table 1 andprovided in the Sequence Listing. These variants will generally bereferred to herein as variant proteins/peptides/polypeptides, orpolymorphic proteins/peptides/polypeptides of the present invention. Theterms “protein,” “peptide,” and “polypeptide” are used hereininterchangeably.

A variant protein of the present invention may be encoded by, forexample, a nonsynonymous nucleotide substitution at any one of the cSNPpositions disclosed herein. In addition, variant proteins may alsoinclude proteins whose expression, structure, and/or function is alteredby a SNP disclosed herein, such as a SNP that creates or destroys a stopcodon, a SNP that affects splicing, and a SNP in control/regulatoryelements, e.g. promoters, enhancers, or transcription factor bindingdomains.

As used herein, a protein or peptide is said to be “isolated” or“purified” when it is substantially free of cellular material orchemical precursors or other chemicals. The variant proteins of thepresent invention can be purified to homogeneity or other lower degreesof purity. The level of purification will be based on the intended use.The key feature is that the preparation allows for the desired functionof the variant protein, even if in the presence of considerable amountsof other components.

As used herein, “substantially free of cellular material” includespreparations of the variant protein having less than about 30% (by dryweight) other proteins (i.e., contaminating protein), less than about20% other proteins, less than about 10% other proteins, or less thanabout 5% other proteins. When the variant protein is recombinantlyproduced, it can also be substantially free of culture medium, i.e.,culture medium represents less than about 20% of the volume of theprotein preparation.

The language “substantially free of chemical precursors or otherchemicals” includes preparations of the variant protein in which it isseparated from chemical precursors or other chemicals that are involvedin its synthesis. In one embodiment, the language “substantially free ofchemical precursors or other chemicals” includes preparations of thevariant protein having less than about 30% (by dry weight) chemicalprecursors or other chemicals, less than about 20% chemical precursorsor other chemicals, less than about 10% chemical precursors or otherchemicals, or less than about 5% chemical precursors or other chemicals.

An isolated variant protein may be purified from cells that naturallyexpress it, purified from cells that have been altered to express it(recombinant host cells), or synthesized using known protein synthesismethods. For example, a nucleic acid molecule containing SNP(s) encodingthe variant protein can be cloned into an expression vector, theexpression vector introduced into a host cell, and the variant proteinexpressed in the host cell. The variant protein can then be isolatedfrom the cells by any appropriate purification scheme using standardprotein purification techniques. Examples of these techniques aredescribed in detail below. Sambrook and Russell, Molecular Cloning: ALaboratory Manual, Cold Spring Harbor Laboratory Press, N.Y. (2000).

The present invention provides isolated variant proteins that comprise,consist of or consist essentially of amino acid sequences that containone or more variant amino acids encoded by one or more codons thatcontain a SNP of the present invention.

Accordingly, the present invention provides variant proteins thatconsist of amino acid sequences that contain one or more amino acidpolymorphisms (or truncations or extensions due to creation ordestruction of a stop codon, respectively) encoded by the SNPs providedin Table 1 and/or Table 2. A protein consists of an amino acid sequencewhen the amino acid sequence is the entire amino acid sequence of theprotein.

The present invention further provides variant proteins that consistessentially of amino acid sequences that contain one or more amino acidpolymorphisms (or truncations or extensions due to creation ordestruction of a stop codon, respectively) encoded by the SNPs providedin Table 1 and/or Table 2. A protein consists essentially of an aminoacid sequence when such an amino acid sequence is present with only afew additional amino acid residues in the final protein.

The present invention further provides variant proteins that compriseamino acid sequences that contain one or more amino acid polymorphisms(or truncations or extensions due to creation or destruction of a stopcodon, respectively) encoded by the SNPs provided in Table 1 and/orTable 2. A protein comprises an amino acid sequence when the amino acidsequence is at least part of the final amino acid sequence of theprotein. In such a fashion, the protein may contain only the variantamino acid sequence or have additional amino acid residues, such as acontiguous encoded sequence that is naturally associated with it orheterologous amino acid residues. Such a protein can have a fewadditional amino acid residues or can comprise many more additionalamino acids. A brief description of how various types of these proteinscan be made and isolated is provided below.

The variant proteins of the present invention can be attached toheterologous sequences to form chimeric or fusion proteins. Suchchimeric and fusion proteins comprise a variant protein operativelylinked to a heterologous protein having an amino acid sequence notsubstantially homologous to the variant protein. “Operatively linked”indicates that the coding sequences for the variant protein and theheterologous protein are ligated in-frame. The heterologous protein canbe fused to the N-terminus or C-terminus of the variant protein. Inanother embodiment, the fusion protein is encoded by a fusionpolynucleotide that is synthesized by conventional techniques includingautomated DNA synthesizers. Alternatively, PCR amplification of genefragments can be carried out using anchor primers which give rise tocomplementary overhangs between two consecutive gene fragments which cansubsequently be annealed and re-amplified to generate a chimeric genesequence. See Ausubel et al., Current Protocols in Molecular Biology(1992). Moreover, many expression vectors are commercially availablethat already encode a fusion moiety (e.g., a GST protein). A variantprotein-encoding nucleic acid can be cloned into such an expressionvector such that the fusion moiety is linked in-frame to the variantprotein.

In many uses, the fusion protein does not affect the activity of thevariant protein. The fusion protein can include, but is not limited to,enzymatic fusion proteins, for example, beta-galactosidase fusions,yeast two-hybrid GAL fusions, poly-His fusions, MYC-tagged, HI-taggedand Ig fusions. Such fusion proteins, particularly poly-His fusions, canfacilitate their purification following recombinant expression. Incertain host cells (e.g., mammalian host cells), expression and/orsecretion of a protein can be increased by using a heterologous signalsequence. Fusion proteins are further described in, for example, Terpe,“Overview of tag protein fusions: from molecular and biochemicalfundamentals to commercial systems,” Appl Microbiol Biotechnol60(5):523-33 (January 2003); Epub Nov. 7, 2002; Graddis et al.,“Designing proteins that work using recombinant technologies,” CurrPharm Biotechnol 3(4):285-97 (December 2002); and Nilsson et al.,“Affinity fusion strategies for detection, purification, andimmobilization of recombinant proteins,” Protein Expr Purif 11(1):1-16(October 1997).

In certain embodiments, novel compositions of the present invention alsorelate to further obvious variants of the variant polypeptides of thepresent invention, such as naturally-occurring mature forms (e.g.,allelic variants), non-naturally occurring recombinantly-derivedvariants, and orthologs and paralogs of such proteins that sharesequence homology. Such variants can readily be generated usingart-known techniques in the fields of recombinant nucleic acidtechnology and protein biochemistry.

Further variants of the variant polypeptides disclosed in Table 1 cancomprise an amino acid sequence that shares at least 70-80%, 80-85%,85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identitywith an amino acid sequence disclosed in Table 1 (or a fragment thereof)and that includes a novel amino acid residue (allele) disclosed in Table1 (which is encoded by a novel SNP allele). Thus, an aspect of thepresent invention that is specifically contemplated are polypeptidesthat have a certain degree of sequence variation compared with thepolypeptide sequences shown in Table 1, but that contain a novel aminoacid residue (allele) encoded by a novel SNP allele disclosed herein. Inother words, as long as a polypeptide contains a novel amino acidresidue disclosed herein, other portions of the polypeptide that flankthe novel amino acid residue can vary to some degree from thepolypeptide sequences shown in Table 1.

Full-length pre-processed forms, as well as mature processed forms, ofproteins that comprise one of the amino acid sequences disclosed hereincan readily be identified as having complete sequence identity to one ofthe variant proteins of the present invention as well as being encodedby the same genetic locus as the variant proteins provided herein.

Orthologs of a variant peptide can readily be identified as having somedegree of significant sequence homology/identity to at least a portionof a variant peptide as well as being encoded by a gene from anotherorganism. Preferred orthologs will be isolated from non-human mammals,preferably primates, for the development of human therapeutic targetsand agents. Such orthologs can be encoded by a nucleic acid sequencethat hybridizes to a variant peptide-encoding nucleic acid moleculeunder moderate to stringent conditions depending on the degree ofrelatedness of the two organisms yielding the homologous proteins.

Variant proteins include, but are not limited to, proteins containingdeletions, additions and substitutions in the amino acid sequence causedby the SNPs of the present invention. One class of substitutions isconserved amino acid substitutions in which a given amino acid in apolypeptide is substituted for another amino acid of likecharacteristics. Typical conservative substitutions are replacements,one for another, among the aliphatic amino acids Ala, Val, Leu, and Ile;interchange of the hydroxyl residues Ser and Thr; exchange of the acidicresidues Asp and Glu; substitution between the amide residues Asn andGln; exchange of the basic residues Lys and Arg; and replacements amongthe aromatic residues Phe and Tyr. Guidance concerning which amino acidchanges are likely to be phenotypically silent are found, for example,in Bowie et al., Science 247:1306-1310 (1990).

Variant proteins can be fully functional or can lack function in one ormore activities, e.g. ability to bind another molecule, ability tocatalyze a substrate, ability to mediate signaling, etc. Fullyfunctional variants typically contain only conservative variations orvariations in non-critical residues or in non-critical regions.Functional variants can also contain substitution of similar amino acidsthat result in no change or an insignificant change in function.Alternatively, such substitutions may positively or negatively affectfunction to some degree. Non-functional variants typically contain oneor more non-conservative amino acid substitutions, deletions,insertions, inversions, truncations or extensions, or a substitution,insertion, inversion, or deletion of a critical residue or in a criticalregion.

Amino acids that are essential for function of a protein can beidentified by methods known in the art, such as site-directedmutagenesis or alanine-scanning mutagenesis, particularly using theamino acid sequence and polymorphism information provided in Table 1.Cunningham et al., Science 244:1081-1085 (1989). The latter procedureintroduces single alanine mutations at every residue in the molecule.The resulting mutant molecules are then tested for biological activitysuch as enzyme activity or in assays such as an in vitro proliferativeactivity. Sites that are critical for binding partner/substrate bindingcan also be determined by structural analysis such as crystallization,nuclear magnetic resonance or photoaffinity labeling. Smith et al., JMol Biol 224:899-904 (1992); de Vos et al., Science 255:306-312 (1992).

Polypeptides can contain amino acids other than the 20 amino acidscommonly referred to as the 20 naturally occurring amino acids. Further,many amino acids, including the terminal amino acids, may be modified bynatural processes, such as processing and other post-translationalmodifications, or by chemical modification techniques well known in theart. Accordingly, the variant proteins of the present invention alsoencompass derivatives or analogs in which a substituted amino acidresidue is not one encoded by the genetic code, in which a substituentgroup is included, in which the mature polypeptide is fused with anothercompound, such as a compound to increase the half-life of thepolypeptide (e.g., polyethylene glycol), or in which additional aminoacids are fused to the mature polypeptide, such as a leader or secretorysequence or a sequence for purification of the mature polypeptide or apro-protein sequence.

Known protein modifications include, but are not limited to,acetylation, acylation, ADP-ribosylation, amidation, covalent attachmentof flavin, covalent attachment of a heme moiety, covalent attachment ofa nucleotide or nucleotide derivative, covalent attachment of a lipid orlipid derivative, covalent attachment of phosphotidylinositol,cross-linking, cyclization, disulfide bond formation, demethylation,formation of covalent crosslinks, formation of cystine, formation ofpyroglutamate, formylation, gamma carboxylation, glycosylation, GPIanchor formation, hydroxylation, iodination, methylation,myristoylation, oxidation, proteolytic processing, phosphorylation,prenylation, racemization, selenoylation, sulfation, transfer-RNAmediated addition of amino acids to proteins such as arginylation, andubiquitination.

Such protein modifications are well known to those of skill in the artand have been described in great detail in the scientific literature.Particularly common modifications, for example glycosylation, lipidattachment, sulfation, gamma-carboxylation of glutamic acid residues,hydroxylation and ADP-ribosylation, are described in most basic texts,such as Proteins—Structure and Molecular Properties 2nd Ed., T. E.Creighton, W.H. Freeman and Company, N.Y. (1993); F. Wold,Posttranslational Covalent Modification of Proteins 1-12, B. C. Johnson,ed., Academic Press, N.Y. (1983); Seifter et al., Meth Enzymol182:626-646 (1990); and Rattan et al., Ann NY Acad Sci 663:48-62 (1992).

The present invention further provides fragments of the variant proteinsin which the fragments contain one or more amino acid sequencevariations (e.g., substitutions, or truncations or extensions due tocreation or destruction of a stop codon) encoded by one or more SNPsdisclosed herein. The fragments to which the invention pertains,however, are not to be construed as encompassing fragments that havebeen disclosed in the prior art before the present invention.

As used herein, a fragment may comprise at least about 4, 8, 10, 12, 14,16, 18, 20, 25, 30, 50, 100 (or any other number in-between) or morecontiguous amino acid residues from a variant protein, wherein at leastone amino acid residue is affected by a SNP of the present invention,e.g., a variant amino acid residue encoded by a nonsynonymous nucleotidesubstitution at a cSNP position provided by the present invention. Thevariant amino acid encoded by a cSNP may occupy any residue positionalong the sequence of the fragment. Such fragments can be chosen basedon the ability to retain one or more of the biological activities of thevariant protein or the ability to perform a function, e.g., act as animmunogen. Particularly important fragments are biologically activefragments. Such fragments will typically comprise a domain or motif of avariant protein of the present invention, e.g., active site,transmembrane domain, or ligand/substrate binding domain. Otherfragments include, but are not limited to, domain or motif-containingfragments, soluble peptide fragments, and fragments containingimmunogenic structures. Predicted domains and functional sites arereadily identifiable by computer programs well known to those of skillin the art (e.g., PROSITE analysis). Current Protocols in ProteinScience, John Wiley & Sons, N.Y. (2002).

Uses of Variant Proteins

The variant proteins of the present invention can be used in a varietyof ways, including but not limited to, in assays to determine thebiological activity of a variant protein, such as in a panel of multipleproteins for high-throughput screening; to raise antibodies or to elicitanother type of immune response; as a reagent (including the labeledreagent) in assays designed to quantitatively determine levels of thevariant protein (or its binding partner) in biological fluids; as amarker for cells or tissues in which it is preferentially expressed(either constitutively or at a particular stage of tissuedifferentiation or development or in a disease state); as a target forscreening for a therapeutic agent; and as a direct therapeutic agent tobe administered into a human subject. Any of the variant proteinsdisclosed herein may be developed into reagent grade or kit format forcommercialization as research products. Methods for performing the useslisted above are well known to those skilled in the art. See, e.g.,Molecular Cloning: A Laboratory Manual, Sambrook and Russell, ColdSpring Harbor Laboratory Press, N.Y. (2000), and Methods in Enzymology:Guide to Molecular Cloning Techniques, S. L. Berger and A. R. Kimmel,eds., Academic Press (1987).

In a specific embodiment of the invention, the methods of the presentinvention include detection of one or more variant proteins disclosedherein. Variant proteins are disclosed in Table 1 and in the SequenceListing as SEQ ID NOS:85-168. Detection of such proteins can beaccomplished using, for example, antibodies, small molecule compounds,aptamers, ligands/substrates, other proteins or protein fragments, orother protein-binding agents. Preferably, protein detection agents arespecific for a variant protein of the present invention and cantherefore discriminate between a variant protein of the presentinvention and the wild-type protein or another variant form. This cangenerally be accomplished by, for example, selecting or designingdetection agents that bind to the region of a protein that differsbetween the variant and wild-type protein, such as a region of a proteinthat contains one or more amino acid substitutions that is/are encodedby a non-synonymous cSNP of the present invention, or a region of aprotein that follows a nonsense mutation-type SNP that creates a stopcodon thereby leading to a shorter polypeptide, or a region of a proteinthat follows a read-through mutation-type SNP that destroys a stop codonthereby leading to a longer polypeptide in which a portion of thepolypeptide is present in one version of the polypeptide but not theother.

In another aspect of the invention, variant proteins of the presentinvention can be used as targets for predicting an individual's responseto statin treatment (particularly for reducing the risk of VT), fordetermining predisposition to VT, for diagnosing VT, or for treatingand/or preventing VT, etc. Accordingly, the invention provides methodsfor detecting the presence of, or levels of, one or more variantproteins of the present invention in a cell, tissue, or organism. Suchmethods typically involve contacting a test sample with an agent (e.g.,an antibody, small molecule compound, or peptide) capable of interactingwith the variant protein such that specific binding of the agent to thevariant protein can be detected. Such an assay can be provided in asingle detection format or a multi-detection format such as an array,for example, an antibody or aptamer array (arrays for protein detectionmay also be referred to as “protein chips”). The variant protein ofinterest can be isolated from a test sample and assayed for the presenceof a variant amino acid sequence encoded by one or more SNPs disclosedby the present invention. The SNPs may cause changes to the protein andthe corresponding protein function/activity, such as throughnon-synonymous substitutions in protein coding regions that can lead toamino acid substitutions, deletions, insertions, and/or rearrangements;formation or destruction of stop codons; or alteration of controlelements such as promoters. SNPs may also cause inappropriatepost-translational modifications.

One preferred agent for detecting a variant protein in a sample is anantibody capable of selectively binding to a variant form of the protein(antibodies are described in greater detail in the next section). Suchsamples include, for example, tissues, cells, and biological fluidsisolated from a subject, as well as tissues, cells and fluids presentwithin a subject.

In vitro methods for detection of the variant proteins associated withstatin response that are disclosed herein and fragments thereof include,but are not limited to, enzyme linked immunosorbent assays (ELISAs),radioimmunoassays (RIA), Western blots, immunoprecipitations,immunofluorescence, and protein arrays/chips (e.g., arrays of antibodiesor aptamers). For further information regarding immunoassays and relatedprotein detection methods, see Current Protocols in Immunology, JohnWiley & Sons, N.Y., and Hage, “Immunoassays,” Anal Chem 15;71(12):294R-304R (June 1999).

Additional analytic methods of detecting amino acid variants include,but are not limited to, altered electrophoretic mobility, alteredtryptic peptide digest, altered protein activity in cell-based orcell-free assay, alteration in ligand or antibody-binding pattern,altered isoelectric point, and direct amino acid sequencing.

Alternatively, variant proteins can be detected in vivo in a subject byintroducing into the subject a labeled antibody (or other type ofdetection reagent) specific for a variant protein. For example, theantibody can be labeled with a radioactive marker whose presence andlocation in a subject can be detected by standard imaging techniques.

Other uses of the variant peptides of the present invention are based onthe class or action of the protein. For example, proteins isolated fromhumans and their mammalian orthologs serve as targets for identifyingagents (e.g., small molecule drugs or antibodies) for use in therapeuticapplications, particularly for modulating a biological or pathologicalresponse in a cell or tissue that expresses the protein. Pharmaceuticalagents can be developed that modulate protein activity.

As an alternative to modulating gene expression, therapeutic compoundscan be developed that modulate protein function. For example, many SNPsdisclosed herein affect the amino acid sequence of the encoded protein(e.g., non-synonymous cSNPs and nonsense mutation-type SNPs). Suchalterations in the encoded amino acid sequence may affect proteinfunction, particularly if such amino acid sequence variations occur infunctional protein domains, such as catalytic domains, ATP-bindingdomains, or ligand/substrate binding domains. It is well established inthe art that variant proteins having amino acid sequence variations infunctional domains can cause or influence pathological conditions. Insuch instances, compounds (e.g., small molecule drugs or antibodies) canbe developed that target the variant protein and modulate (e.g., up- ordown-regulate) protein function/activity.

The therapeutic methods of the present invention further include methodsthat target one or more variant proteins of the present invention.Variant proteins can be targeted using, for example, small moleculecompounds, antibodies, aptamers, ligands/substrates, other proteins, orother protein-binding agents. Additionally, the skilled artisan willrecognize that the novel protein variants (and polymorphic nucleic acidmolecules) disclosed in Table 1 may themselves be directly used astherapeutic agents by acting as competitive inhibitors of correspondingart-known proteins (or nucleic acid molecules such as mRNA molecules).

The variant proteins of the present invention are particularly useful indrug screening assays, in cell-based or cell-free systems. Cell-basedsystems can utilize cells that naturally express the protein, a biopsyspecimen, or cell cultures. In one embodiment, cell-based assays involverecombinant host cells expressing the variant protein. Cell-free assayscan be used to detect the ability of a compound to directly bind to avariant protein or to the corresponding SNP-containing nucleic acidfragment that encodes the variant protein.

A variant protein of the present invention, as well as appropriatefragments thereof, can be used in high-throughput screening assays totest candidate compounds for the ability to bind and/or modulate theactivity of the variant protein. These candidate compounds can befurther screened against a protein having normal function (e.g., awild-type/non-variant protein) to further determine the effect of thecompound on the protein activity. Furthermore, these compounds can betested in animal or invertebrate systems to determine in vivoactivity/effectiveness. Compounds can be identified that activate(agonists) or inactivate (antagonists) the variant protein, anddifferent compounds can be identified that cause various degrees ofactivation or inactivation of the variant protein.

Further, the variant proteins can be used to screen a compound for theability to stimulate or inhibit interaction between the variant proteinand a target molecule that normally interacts with the protein. Thetarget can be a ligand, a substrate or a binding partner that theprotein normally interacts with (for example, epinephrine ornorepinephrine). Such assays typically include the steps of combiningthe variant protein with a candidate compound under conditions thatallow the variant protein, or fragment thereof, to interact with thetarget molecule, and to detect the formation of a complex between theprotein and the target or to detect the biochemical consequence of theinteraction with the variant protein and the target, such as any of theassociated effects of signal transduction.

Candidate compounds include, for example, 1) peptides such as solublepeptides, including Ig-tailed fusion peptides and members of randompeptide libraries (see, e.g., Lam et al., Nature 354:82-84 (1991);Houghten et al., Nature 354:84-86 (1991)) and combinatorialchemistry-derived molecular libraries made of D- and/or L-configurationamino acids; 2) phosphopeptides (e.g., members of random and partiallydegenerate, directed phosphopeptide libraries, see, e.g., Songyang etal., Cell 72:767-778 (1993)); 3) antibodies (e.g., polyclonal,monoclonal, humanized, anti-idiotypic, chimeric, and single chainantibodies as well as Fab, F(ab′)₂, Fab expression library fragments,and epitope-binding fragments of antibodies); and 4) small organic andinorganic molecules (e.g., molecules obtained from combinatorial andnatural product libraries).

One candidate compound is a soluble fragment of the variant protein thatcompetes for ligand binding. Other candidate compounds include mutantproteins or appropriate fragments containing mutations that affectvariant protein function and thus compete for ligand. Accordingly, afragment that competes for ligand, for example with a higher affinity,or a fragment that binds ligand but does not allow release, isencompassed by the invention.

The invention further includes other end point assays to identifycompounds that modulate (stimulate or inhibit) variant protein activity.The assays typically involve an assay of events in the signaltransduction pathway that indicate protein activity. Thus, theexpression of genes that are up or down-regulated in response to thevariant protein dependent signal cascade can be assayed. In oneembodiment, the regulatory region of such genes can be operably linkedto a marker that is easily detectable, such as luciferase.Alternatively, phosphorylation of the variant protein, or a variantprotein target, could also be measured. Any of the biological orbiochemical functions mediated by the variant protein can be used as anendpoint assay. These include all of the biochemical or biologicalevents described herein, in the references cited herein, incorporated byreference for these endpoint assay targets, and other functions known tothose of ordinary skill in the art.

Binding and/or activating compounds can also be screened by usingchimeric variant proteins in which an amino terminal extracellulardomain or parts thereof, an entire transmembrane domain or subregions,and/or the carboxyl terminal intracellular domain or parts thereof, canbe replaced by heterologous domains or subregions. For example, asubstrate-binding region can be used that interacts with a differentsubstrate than that which is normally recognized by a variant protein.Accordingly, a different set of signal transduction components isavailable as an end-point assay for activation. This allows for assaysto be performed in other than the specific host cell from which thevariant protein is derived.

The variant proteins are also useful in competition binding assays inmethods designed to discover compounds that interact with the variantprotein. Thus, a compound can be exposed to a variant protein underconditions that allow the compound to bind or to otherwise interact withthe variant protein. A binding partner, such as ligand, that normallyinteracts with the variant protein is also added to the mixture. If thetest compound interacts with the variant protein or its binding partner,it decreases the amount of complex formed or activity from the variantprotein. This type of assay is particularly useful in screening forcompounds that interact with specific regions of the variant protein.Hodgson, Bio/technology, 10(9), 973-80 (September 1992).

To perform cell-free drug screening assays, it is sometimes desirable toimmobilize either the variant protein or a fragment thereof, or itstarget molecule, to facilitate separation of complexes from uncomplexedforms of one or both of the proteins, as well as to accommodateautomation of the assay. Any method for immobilizing proteins onmatrices can be used in drug screening assays. In one embodiment, afusion protein containing an added domain allows the protein to be boundto a matrix. For example, glutathione-S-transferase/¹²⁵I fusion proteinscan be adsorbed onto glutathione sepharose beads (Sigma Chemical, St.Louis, Mo.) or glutathione derivatized microtitre plates, which are thencombined with the cell lysates (e.g., ³⁵S-labeled) and a candidatecompound, such as a drug candidate, and the mixture incubated underconditions conducive to complex formation (e.g., at physiologicalconditions for salt and pH). Following incubation, the beads can bewashed to remove any unbound label, and the matrix immobilized andradiolabel determined directly, or in the supernatant after thecomplexes are dissociated. Alternatively, the complexes can bedissociated from the matrix, separated by SDS-PAGE, and the level ofbound material found in the bead fraction quantitated from the gel usingstandard electrophoretic techniques.

Either the variant protein or its target molecule can be immobilizedutilizing conjugation of biotin and streptavidin. Alternatively,antibodies reactive with the variant protein but which do not interferewith binding of the variant protein to its target molecule can bederivatized to the wells of the plate, and the variant protein trappedin the wells by antibody conjugation. Preparations of the targetmolecule and a candidate compound are incubated in the variantprotein-presenting wells and the amount of complex trapped in the wellcan be quantitated. Methods for detecting such complexes, in addition tothose described above for the GST-immobilized complexes, includeimmunodetection of complexes using antibodies reactive with the proteintarget molecule, or which are reactive with variant protein and competewith the target molecule, and enzyme-linked assays that rely ondetecting an enzymatic activity associated with the target molecule.

Modulators of variant protein activity identified according to thesedrug screening assays can be used to treat a subject with a disordermediated by the protein pathway, such as VT. These methods of treatmenttypically include the steps of administering the modulators of proteinactivity in a pharmaceutical composition to a subject in need of suchtreatment.

The variant proteins, or fragments thereof, disclosed herein canthemselves be directly used to treat a disorder characterized by anabsence of, inappropriate, or unwanted expression or activity of thevariant protein. Accordingly, methods for treatment include the use of avariant protein disclosed herein or fragments thereof.

In yet another aspect of the invention, variant proteins can be used as“bait proteins” in a two-hybrid assay or three-hybrid assay to identifyother proteins that bind to or interact with the variant protein and areinvolved in variant protein activity. See, e.g., U.S. Pat. No.5,283,317; Zervos et al., Cell 72:223-232 (1993); Madura et al., J BiolChem 268:12046-12054 (1993); Bartel et al., Biotechniques 14:920-924(1993); Iwabuchi et al., Oncogene 8:1693-1696 (1993); and Brent, WO94/10300. Such variant protein-binding proteins are also likely to beinvolved in the propagation of signals by the variant proteins orvariant protein targets as, for example, elements of a protein-mediatedsignaling pathway. Alternatively, such variant protein-binding proteinsare inhibitors of the variant protein.

The two-hybrid system is based on the modular nature of mosttranscription factors, which typically consist of separable DNA-bindingand activation domains. Briefly, the assay typically utilizes twodifferent DNA constructs. In one construct, the gene that codes for avariant protein is fused to a gene encoding the DNA binding domain of aknown transcription factor (e.g., GAL-4). In the other construct, a DNAsequence, from a library of DNA sequences, that encodes an unidentifiedprotein (“prey” or “sample”) is fused to a gene that codes for theactivation domain of the known transcription factor. If the “bait” andthe “prey” proteins are able to interact, in vivo, forming a variantprotein-dependent complex, the DNA-binding and activation domains of thetranscription factor are brought into close proximity. This proximityallows transcription of a reporter gene (e.g., LacZ) that is operablylinked to a transcriptional regulatory site responsive to thetranscription factor. Expression of the reporter gene can be detected,and cell colonies containing the functional transcription factor can beisolated and used to obtain the cloned gene that encodes the proteinthat interacts with the variant protein.

Antibodies Directed to Variant Proteins

The present invention also provides antibodies that selectively bind tothe variant proteins disclosed herein and fragments thereof. Suchantibodies may be used to quantitatively or qualitatively detect thevariant proteins of the present invention. As used herein, an antibodyselectively binds a target variant protein when it binds the variantprotein and does not significantly bind to non-variant proteins, i.e.,the antibody does not significantly bind to normal, wild-type, orart-known proteins that do not contain a variant amino acid sequence dueto one or more SNPs of the present invention (variant amino acidsequences may be due to, for example, nonsynonymous cSNPs, nonsense SNPsthat create a stop codon, thereby causing a truncation of a polypeptideor SNPs that cause read-through mutations resulting in an extension of apolypeptide).

As used herein, an antibody is defined in terms consistent with thatrecognized in the art: they are multi-subunit proteins produced by anorganism in response to an antigen challenge. The antibodies of thepresent invention include both monoclonal antibodies and polyclonalantibodies, as well as antigen-reactive proteolytic fragments of suchantibodies, such as Fab, F(ab)′₂, and Fv fragments. In addition, anantibody of the present invention further includes any of a variety ofengineered antigen-binding molecules such as a chimeric antibody (U.S.Pat. Nos. 4,816,567 and 4,816,397; Morrison et al., Proc Natl Acad SciUSA 81:6851 (1984); Neuberger et al., Nature 312:604 (1984)), ahumanized antibody (U.S. Pat. Nos. 5,693,762; 5,585,089 and 5,565,332),a single-chain Fv (U.S. Pat. No. 4,946,778; Ward et al., Nature 334:544(1989)), a bispecific antibody with two binding specificities (Segal etal., J Immunol Methods 248:1 (2001); Carter, J Immunol Methods 248:7(2001)), a diabody, a triabody, and a tetrabody (Todorovska et al., JImmunol Methods 248:47 (2001)), as well as a Fab conjugate (dimer ortrimer), and a minibody.

Many methods are known in the art for generating and/or identifyingantibodies to a given target antigen. Harlow, Antibodies, Cold SpringHarbor Press, N.Y. (1989). In general, an isolated peptide (e.g., avariant protein of the present invention) is used as an immunogen and isadministered to a mammalian organism, such as a rat, rabbit, hamster ormouse. Either a full-length protein, an antigenic peptide fragment(e.g., a peptide fragment containing a region that varies between avariant protein and a corresponding wild-type protein), or a fusionprotein can be used. A protein used as an immunogen may benaturally-occurring, synthetic or recombinantly produced, and may beadministered in combination with an adjuvant, including but not limitedto, Freund's (complete and incomplete), mineral gels such as aluminumhydroxide, surface active substance such as lysolecithin, pluronicpolyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin,dinitrophenol, and the like.

Monoclonal antibodies can be produced by hybridoma technology, whichimmortalizes cells secreting a specific monoclonal antibody. Kohler andMilstein, Nature 256:495 (1975). The immortalized cell lines can becreated in vitro by fusing two different cell types, typicallylymphocytes, and tumor cells. The hybridoma cells may be cultivated invitro or in vivo. Additionally, fully human antibodies can be generatedby transgenic animals. He et al., J Immunol 169:595 (2002). Fd phage andFd phagemid technologies may be used to generate and select recombinantantibodies in vitro. Hoogenboom and Chames, Immunol Today 21:371 (2000);Liu et al., J Mol Biol 315:1063 (2002). The complementarity-determiningregions of an antibody can be identified, and synthetic peptidescorresponding to such regions may be used to mediate antigen binding.U.S. Pat. No. 5,637,677.

Antibodies are preferably prepared against regions or discrete fragmentsof a variant protein containing a variant amino acid sequence ascompared to the corresponding wild-type protein (e.g., a region of avariant protein that includes an amino acid encoded by a nonsynonymouscSNP, a region affected by truncation caused by a nonsense SNP thatcreates a stop codon, or a region resulting from the destruction of astop codon due to read-through mutation caused by a SNP). Furthermore,preferred regions will include those involved in function/activityand/or protein/binding partner interaction. Such fragments can beselected on a physical property, such as fragments corresponding toregions that are located on the surface of the protein, e.g.,hydrophilic regions, or can be selected based on sequence uniqueness, orbased on the position of the variant amino acid residue(s) encoded bythe SNPs provided by the present invention. An antigenic fragment willtypically comprise at least about 8-10 contiguous amino acid residues inwhich at least one of the amino acid residues is an amino acid affectedby a SNP disclosed herein. The antigenic peptide can comprise, however,at least 12, 14, 16, 20, 25, 50, 100 (or any other number in-between) ormore amino acid residues, provided that at least one amino acid isaffected by a SNP disclosed herein.

Detection of an antibody of the present invention can be facilitated bycoupling (i.e., physically linking) the antibody or an antigen-reactivefragment thereof to a detectable substance. Detectable substancesinclude, but are not limited to, various enzymes, prosthetic groups,fluorescent materials, luminescent materials, bioluminescent materials,and radioactive materials. Examples of suitable enzymes includehorseradish peroxidase, alkaline phosphatase, (3-galactosidase, oracetylcholinesterase; examples of suitable prosthetic group complexesinclude streptavidin/biotin and avidin/biotin; examples of suitablefluorescent materials include umbelliferone, fluorescein, fluoresceinisothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansylchloride or phycoerythrin; an example of a luminescent material includesluminol; examples of bioluminescent materials include luciferase,luciferin, and aequorin, and examples of suitable radioactive materialinclude ¹²⁵I, ¹³¹I, ³⁵S or ³H.

Antibodies, particularly the use of antibodies as therapeutic agents,are reviewed in: Morgan, “Antibody therapy for Alzheimer's disease,”Expert Rev Vaccines (1):53-9 (February 2003); Ross et al., “Anticancerantibodies,” Am J Clin Pathol 119(4):472-85 (April 2003); Goldenberg,“Advancing role of radiolabeled antibodies in the therapy of cancer,”Cancer Immunol Immunother 52(5):281-96 (May 2003); Epub Mar. 11, 2003;Ross et al., “Antibody-based therapeutics in oncology,” Expert RevAnticancer Ther 3(1):107-21 (February 2003); Cao et al., “Bispecificantibody conjugates in therapeutics,” Adv Drug Deliv Rev 55(2):171-97(February 2003); von Mehren et al., “Monoclonal antibody therapy forcancer,” Annu Rev Med 54:343-69 (2003); Epub Dec. 3, 2001; Hudson etal., “Engineered antibodies,” Nat Med 9(1):129-34 (January 2003); Brekkeet al., “Therapeutic antibodies for human diseases at the dawn of thetwenty-first century,” Nat Rev Drug Discov 2(1):52-62 (January 2003);Erratum in: Nat Rev Drug Discov 2(3):240 (March 2003); Houdebine,“Antibody manufacture in transgenic animals and comparisons with othersystems,” Curr Opin Biotechnol 13(6):625-9 (December 2002); Andreakos etal., “Monoclonal antibodies in immune and inflammatory diseases,” CurrOpin Biotechnol 13(6):615-20 (December 2002); Kellermann et al.,“Antibody discovery: the use of transgenic mice to generate humanmonoclonal antibodies for therapeutics,” Curr Opin Biotechnol13(6):593-7 (December 2002); Pini et al., “Phage display and colonyfilter screening for high-throughput selection of antibody libraries,”Comb Chem High Throughput Screen 5(7):503-10 (November 2002); Batra etal., “Pharmacokinetics and biodistribution of genetically engineeredantibodies,” Curr Opin Biotechnol 13(6):603-8 (December 2002); andTangri et al., “Rationally engineered proteins or antibodies with absentor reduced immunogenicity,” Curr Med Chem 9(24):2191-9 (December 2002).

Uses of Antibodies

Antibodies can be used to isolate the variant proteins of the presentinvention from a natural cell source or from recombinant host cells bystandard techniques, such as affinity chromatography orimmunoprecipitation. In addition, antibodies are useful for detectingthe presence of a variant protein of the present invention in cells ortissues to determine the pattern of expression of the variant proteinamong various tissues in an organism and over the course of normaldevelopment or disease progression. Further, antibodies can be used todetect variant protein in situ, in vitro, in a bodily fluid, or in acell lysate or supernatant in order to evaluate the amount and patternof expression. Also, antibodies can be used to assess abnormal tissuedistribution, abnormal expression during development, or expression inan abnormal condition, such as in VT, or during statin treatment.Additionally, antibody detection of circulating fragments of thefull-length variant protein can be used to identify turnover.

Antibodies to the variant proteins of the present invention are alsouseful in pharmacogenomic analysis. Thus, antibodies against variantproteins encoded by alternative SNP alleles can be used to identifyindividuals that require modified treatment modalities.

Further, antibodies can be used to assess expression of the variantprotein in disease states such as in active stages of the disease or inan individual with a predisposition to a disease related to theprotein's function, such as VT, or during the course of a treatmentregime, such as during statin treatment. Antibodies specific for avariant protein encoded by a SNP-containing nucleic acid molecule of thepresent invention can be used to assay for the presence of the variantprotein, such as to determine an individual's response to statintreatment (particularly for reducing their risk for VT) or to diagnoseVT or predisposition/susceptibility to VT, as indicated by the presenceof the variant protein.

Antibodies are also useful as diagnostic tools for evaluating thevariant proteins in conjunction with analysis by electrophoreticmobility, isoelectric point, tryptic peptide digest, and other physicalassays well known in the art.

Antibodies are also useful for tissue typing. Thus, where a specificvariant protein has been correlated with expression in a specifictissue, antibodies that are specific for this protein can be used toidentify a tissue type.

Antibodies can also be used to assess aberrant subcellular localizationof a variant protein in cells in various tissues. The diagnostic usescan be applied, not only in genetic testing, but also in monitoring atreatment modality. Accordingly, where treatment is ultimately aimed atcorrecting the expression level or the presence of variant protein oraberrant tissue distribution or developmental expression of a variantprotein, antibodies directed against the variant protein or relevantfragments can be used to monitor therapeutic efficacy.

The antibodies are also useful for inhibiting variant protein function,for example, by blocking the binding of a variant protein to a bindingpartner. These uses can also be applied in a therapeutic context inwhich treatment involves inhibiting a variant protein's function. Anantibody can be used, for example, to block or competitively inhibitbinding, thus modulating (agonizing or antagonizing) the activity of avariant protein. Antibodies can be prepared against specific variantprotein fragments containing sites required for function or against anintact variant protein that is associated with a cell or cell membrane.For in vivo administration, an antibody may be linked with an additionaltherapeutic payload such as a radionuclide, an enzyme, an immunogenicepitope, or a cytotoxic agent. Suitable cytotoxic agents include, butare not limited to, bacterial toxin such as diphtheria, and plant toxinsuch as ricin. The in vivo half-life of an antibody or a fragmentthereof may be lengthened by pegylation through conjugation topolyethylene glycol. Leong et al., Cytokine 16:106 (2001).

The invention also encompasses kits for using antibodies, such as kitsfor detecting the presence of a variant protein in a test sample. Anexemplary kit can comprise antibodies such as a labeled or labelableantibody and a compound or agent for detecting variant proteins in abiological sample; means for determining the amount, or presence/absenceof variant protein in the sample; means for comparing the amount ofvariant protein in the sample with a standard; and instructions for use.

Vectors and Host Cells

The present invention also provides vectors containing theSNP-containing nucleic acid molecules described herein. The term“vector” refers to a vehicle, preferably a nucleic acid molecule, whichcan transport a SNP-containing nucleic acid molecule. When the vector isa nucleic acid molecule, the SNP-containing nucleic acid molecule can becovalently linked to the vector nucleic acid. Such vectors include, butare not limited to, a plasmid, single or double stranded phage, a singleor double stranded RNA or DNA viral vector, or artificial chromosome,such as a BAC, PAC, YAC, or MAC.

A vector can be maintained in a host cell as an extrachromosomal elementwhere it replicates and produces additional copies of the SNP-containingnucleic acid molecules. Alternatively, the vector may integrate into thehost cell genome and produce additional copies of the SNP-containingnucleic acid molecules when the host cell replicates.

The invention provides vectors for the maintenance (cloning vectors) orvectors for expression (expression vectors) of the SNP-containingnucleic acid molecules. The vectors can function in prokaryotic oreukaryotic cells or in both (shuttle vectors).

Expression vectors typically contain cis-acting regulatory regions thatare operably linked in the vector to the SNP-containing nucleic acidmolecules such that transcription of the SNP-containing nucleic acidmolecules is allowed in a host cell. The SNP-containing nucleic acidmolecules can also be introduced into the host cell with a separatenucleic acid molecule capable of affecting transcription. Thus, thesecond nucleic acid molecule may provide a trans-acting factorinteracting with the cis-regulatory control region to allowtranscription of the SNP-containing nucleic acid molecules from thevector. Alternatively, a trans-acting factor may be supplied by the hostcell. Finally, a trans-acting factor can be produced from the vectoritself. It is understood, however, that in some embodiments,transcription and/or translation of the nucleic acid molecules can occurin a cell-free system.

The regulatory sequences to which the SNP-containing nucleic acidmolecules described herein can be operably linked include promoters fordirecting mRNA transcription. These include, but are not limited to, theleft promoter from bacteriophage λ, the lac, TRP, and TAC promoters fromE. coli, the early and late promoters from SV40, the CMV immediate earlypromoter, the adenovirus early and late promoters, and retroviruslong-terminal repeats.

In addition to control regions that promote transcription, expressionvectors may also include regions that modulate transcription, such asrepressor binding sites and enhancers. Examples include the SV40enhancer, the cytomegalovirus immediate early enhancer, polyomaenhancer, adenovirus enhancers, and retrovirus LTR enhancers.

In addition to containing sites for transcription initiation andcontrol, expression vectors can also contain sequences necessary fortranscription termination and, in the transcribed region, aribosome-binding site for translation. Other regulatory control elementsfor expression include initiation and termination codons as well aspolyadenylation signals. A person of ordinary skill in the art would beaware of the numerous regulatory sequences that are useful in expressionvectors. See, e.g., Sambrook and Russell, Molecular Cloning: ALaboratory Manual, Cold Spring Harbor Laboratory Press, N.Y. (2000).

A variety of expression vectors can be used to express a SNP-containingnucleic acid molecule. Such vectors include chromosomal, episomal, andvirus-derived vectors, for example, vectors derived from bacterialplasmids, from bacteriophage, from yeast episomes, from yeastchromosomal elements, including yeast artificial chromosomes, fromviruses such as baculoviruses, papovaviruses such as SV40, Vacciniaviruses, adenoviruses, poxviruses, pseudorabies viruses, andretroviruses. Vectors can also be derived from combinations of thesesources such as those derived from plasmid and bacteriophage geneticelements, e.g., cosmids and phagemids. Appropriate cloning andexpression vectors for prokaryotic and eukaryotic hosts are described inSambrook and Russell, Molecular Cloning: A Laboratory Manual, ColdSpring Harbor Laboratory Press, N.Y. (2000).

The regulatory sequence in a vector may provide constitutive expressionin one or more host cells (e.g., tissue specific expression) or mayprovide for inducible expression in one or more cell types such as bytemperature, nutrient additive, or exogenous factor, e.g., a hormone orother ligand. A variety of vectors that provide constitutive orinducible expression of a nucleic acid sequence in prokaryotic andeukaryotic host cells are well known to those of ordinary skill in theart.

A SNP-containing nucleic acid molecule can be inserted into the vectorby methodology well-known in the art. Generally, the SNP-containingnucleic acid molecule that will ultimately be expressed is joined to anexpression vector by cleaving the SNP-containing nucleic acid moleculeand the expression vector with one or more restriction enzymes and thenligating the fragments together. Procedures for restriction enzymedigestion and ligation are well known to those of ordinary skill in theart.

The vector containing the appropriate nucleic acid molecule can beintroduced into an appropriate host cell for propagation or expressionusing well-known techniques. Bacterial host cells include, but are notlimited to, Escherichia coli, Streptomyces spp., and Salmonellatyphimurium. Eukaryotic host cells include, but are not limited to,yeast, insect cells such as Drosophila spp., animal cells such as COSand CHO cells, and plant cells.

As described herein, it may be desirable to express the variant peptideas a fusion protein. Accordingly, the invention provides fusion vectorsthat allow for the production of the variant peptides. Fusion vectorscan, for example, increase the expression of a recombinant protein,increase the solubility of the recombinant protein, and aid in thepurification of the protein by acting, for example, as a ligand foraffinity purification. A proteolytic cleavage site may be introduced atthe junction of the fusion moiety so that the desired variant peptidecan ultimately be separated from the fusion moiety. Proteolytic enzymessuitable for such use include, but are not limited to, factor Xa,thrombin, and enterokinase. Typical fusion expression vectors includepGEX (Smith et al., Gene 67:31-40 (1988)), pMAL (New England Biolabs,Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) which fuseglutathione S-transferase (GST), maltose E binding protein, or proteinA, respectively, to the target recombinant protein. Examples of suitableinducible non-fusion E. coli expression vectors include pTrc (Amann etal., Gene 69:301-315 (1988)) and pET 11d (Studier et al., GeneExpression Technology: Methods in Enzymology 185:60-89 (1990)).

Recombinant protein expression can be maximized in a bacterial host byproviding a genetic background wherein the host cell has an impairedcapacity to proteolytically cleave the recombinant protein (S.Gottesman, Gene Expression Technology: Methods in Enzymology185:119-128, Academic Press, Calif. (1990)). Alternatively, the sequenceof the SNP-containing nucleic acid molecule of interest can be alteredto provide preferential codon usage for a specific host cell, forexample, E. coli. Wada et al., Nucleic Acids Res 20:2111-2118 (1992).

The SNP-containing nucleic acid molecules can also be expressed byexpression vectors that are operative in yeast. Examples of vectors forexpression in yeast (e.g., S. cerevisiae) include pYepSec1 (Baldari etal., EMBO J 6:229-234 (1987)), pMFa (Kurjan et al., Cell 30:933-943(1982)), pJRY88 (Schultz et al., Gene 54:113-123 (1987)), and pYES2(Invitrogen Corporation, San Diego, Calif.).

The SNP-containing nucleic acid molecules can also be expressed ininsect cells using, for example, baculovirus expression vectors.Baculovirus vectors available for expression of proteins in culturedinsect cells (e.g., Sf 9 cells) include the pAc series (Smith et al.,Mol Cell Biol 3:2156-2165 (1983)) and the pVL series (Lucklow et al.,Virology 170:31-39 (1989)).

In certain embodiments of the invention, the SNP-containing nucleic acidmolecules described herein are expressed in mammalian cells usingmammalian expression vectors. Examples of mammalian expression vectorsinclude pCDM8 (B. Seed, Nature 329:840(1987)) and pMT2PC (Kaufman etal., EMBO J 6:187-195 (1987)).

The invention also encompasses vectors in which the SNP-containingnucleic acid molecules described herein are cloned into the vector inreverse orientation, but operably linked to a regulatory sequence thatpermits transcription of antisense RNA. Thus, an antisense transcriptcan be produced to the SNP-containing nucleic acid sequences describedherein, including both coding and non-coding regions. Expression of thisantisense RNA is subject to each of the parameters described above inrelation to expression of the sense RNA (regulatory sequences,constitutive or inducible expression, tissue-specific expression).

The invention also relates to recombinant host cells containing thevectors described herein. Host cells therefore include, for example,prokaryotic cells, lower eukaryotic cells such as yeast, othereukaryotic cells such as insect cells, and higher eukaryotic cells suchas mammalian cells.

The recombinant host cells can be prepared by introducing the vectorconstructs described herein into the cells by techniques readilyavailable to persons of ordinary skill in the art. These include, butare not limited to, calcium phosphate transfection,DEAE-dextran-mediated transfection, cationic lipid-mediatedtransfection, electroporation, transduction, infection, lipofection, andother techniques such as those described in Sambrook and Russell,Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory,Cold Spring Harbor Laboratory Press, N.Y. (2000).

Host cells can contain more than one vector. Thus, differentSNP-containing nucleotide sequences can be introduced in differentvectors into the same cell. Similarly, the SNP-containing nucleic acidmolecules can be introduced either alone or with other nucleic acidmolecules that are not related to the SNP-containing nucleic acidmolecules, such as those providing trans-acting factors for expressionvectors. When more than one vector is introduced into a cell, thevectors can be introduced independently, co-introduced, or joined to thenucleic acid molecule vector.

In the case of bacteriophage and viral vectors, these can be introducedinto cells as packaged or encapsulated virus by standard procedures forinfection and transduction. Viral vectors can be replication-competentor replication-defective. In the case in which viral replication isdefective, replication can occur in host cells that provide functionsthat complement the defects.

Vectors generally include selectable markers that enable the selectionof the subpopulation of cells that contain the recombinant vectorconstructs. The marker can be inserted in the same vector that containsthe SNP-containing nucleic acid molecules described herein or may be ina separate vector. Markers include, for example, tetracycline orampicillin-resistance genes for prokaryotic host cells, anddihydrofolate reductase or neomycin resistance genes for eukaryotic hostcells. However, any marker that provides selection for a phenotypictrait can be effective.

While the mature variant proteins can be produced in bacteria, yeast,mammalian cells, and other cells under the control of the appropriateregulatory sequences, cell-free transcription and translation systemscan also be used to produce these variant proteins using RNA derivedfrom the DNA constructs described herein.

Where secretion of the variant protein is desired, which is difficult toachieve with multi-transmembrane domain containing proteins such asG-protein-coupled receptors (GPCRs), appropriate secretion signals canbe incorporated into the vector. The signal sequence can be endogenousto the peptides or heterologous to these peptides.

Where the variant protein is not secreted into the medium, the proteincan be isolated from the host cell by standard disruption procedures,including freeze/thaw, sonication, mechanical disruption, use of lysingagents, and the like. The variant protein can then be recovered andpurified by well-known purification methods including, for example,ammonium sulfate precipitation, acid extraction, anion or cationicexchange chromatography, phosphocellulose chromatography,hydrophobic-interaction chromatography, affinity chromatography,hydroxylapatite chromatography, lectin chromatography, or highperformance liquid chromatography.

It is also understood that, depending upon the host cell in whichrecombinant production of the variant proteins described herein occurs,they can have various glycosylation patterns, or may benon-glycosylated, as when produced in bacteria. In addition, the variantproteins may include an initial modified methionine in some cases as aresult of a host-mediated process.

For further information regarding vectors and host cells, see CurrentProtocols in Molecular Biology, John Wiley & Sons, N.Y.

Uses of Vectors and Host Cells, and Transgenic Animals

Recombinant host cells that express the variant proteins describedherein have a variety of uses. For example, the cells are useful forproducing a variant protein that can be further purified into apreparation of desired amounts of the variant protein or fragmentsthereof. Thus, host cells containing expression vectors are useful forvariant protein production.

Host cells are also useful for conducting cell-based assays involvingthe variant protein or variant protein fragments, such as thosedescribed above as well as other formats known in the art. Thus, arecombinant host cell expressing a variant protein is useful forassaying compounds that stimulate or inhibit variant protein function.Such an ability of a compound to modulate variant protein function maynot be apparent from assays of the compound on the native/wild-typeprotein, or from cell-free assays of the compound. Recombinant hostcells are also useful for assaying functional alterations in the variantproteins as compared with a known function.

Genetically-engineered host cells can be further used to producenon-human transgenic animals. A transgenic animal is preferably anon-human mammal, for example, a rodent, such as a rat or mouse, inwhich one or more of the cells of the animal include a transgene. Atransgene is exogenous DNA containing a SNP of the present inventionwhich is integrated into the genome of a cell from which a transgenicanimal develops and which remains in the genome of the mature animal inone or more of its cell types or tissues. Such animals are useful forstudying the function of a variant protein in vivo, and identifying andevaluating modulators of variant protein activity. Other examples oftransgenic animals include, but are not limited to, non-human primates,sheep, dogs, cows, goats, chickens, and amphibians. Transgenic non-humanmammals such as cows and goats can be used to produce variant proteinswhich can be secreted in the animal's milk and then recovered.

A transgenic animal can be produced by introducing a SNP-containingnucleic acid molecule into the male pronuclei of a fertilized oocyte,e.g., by microinjection or retroviral infection, and allowing the oocyteto develop in a pseudopregnant female foster animal. Any nucleic acidmolecules that contain one or more SNPs of the present invention canpotentially be introduced as a transgene into the genome of a non-humananimal.

Any of the regulatory or other sequences useful in expression vectorscan form part of the transgenic sequence. This includes intronicsequences and polyadenylation signals, if not already included. Atissue-specific regulatory sequence(s) can be operably linked to thetransgene to direct expression of the variant protein in particularcells or tissues.

Methods for generating transgenic animals via embryo manipulation andmicroinjection, particularly animals such as mice, have becomeconventional in the art and are described, for example, in U.S. Pat.Nos. 4,736,866 and 4,870,009, both by Leder et al.; U.S. Pat. No.4,873,191 by Wagner et al., and in B. Hogan, Manipulating the MouseEmbryo, Cold Spring Harbor Laboratory Press, N.Y. (1986). Similarmethods are used for production of other transgenic animals. Atransgenic founder animal can be identified based upon the presence ofthe transgene in its genome and/or expression of transgenic mRNA intissues or cells of the animals. A transgenic founder animal can then beused to breed additional animals carrying the transgene. Moreover,transgenic animals carrying a transgene can further be bred to othertransgenic animals carrying other transgenes. A transgenic animal alsoincludes a non-human animal in which the entire animal or tissues in theanimal have been produced using the homologously recombinant host cellsdescribed herein.

In another embodiment, transgenic non-human animals can be producedwhich contain selected systems that allow for regulated expression ofthe transgene. One example of such a system is the cre/loxP recombinasesystem of bacteriophage P1. Lakso et al., PNAS 89:6232-6236 (1992).Another example of a recombinase system is the FLP recombinase system ofS. cerevisiae. O'Gorman et al., Science 251:1351-1355 (1991). If acre/loxP recombinase system is used to regulate expression of thetransgene, animals containing transgenes encoding both the Crerecombinase and a selected protein are generally needed. Such animalscan be provided through the construction of “double” transgenic animals,e.g., by mating two transgenic animals, one containing a transgeneencoding a selected variant protein and the other containing a transgeneencoding a recombinase.

Clones of the non-human transgenic animals described herein can also beproduced according to the methods described, for example, in I. Wilmutet al., Nature 385:810-813 (1997) and PCT International Publication Nos.WO 97/07668 and WO 97/07669. In brief, a cell (e.g., a somatic cell)from the transgenic animal can be isolated and induced to exit thegrowth cycle and enter G₀ phase. The quiescent cell can then be fused,e.g., through the use of electrical pulses, to an enucleated oocyte froman animal of the same species from which the quiescent cell is isolated.The reconstructed oocyte is then cultured such that it develops tomorula or blastocyst and then transferred to pseudopregnant femalefoster animal. The offspring born of this female foster animal will be aclone of the animal from which the cell (e.g., a somatic cell) isisolated.

Transgenic animals containing recombinant cells that express the variantproteins described herein are useful for conducting the assays describedherein in an in vivo context. Accordingly, the various physiologicalfactors that are present in vivo and that could influence ligand orsubstrate binding, variant protein activation, signal transduction, orother processes or interactions, may not be evident from in vitrocell-free or cell-based assays. Thus, non-human transgenic animals ofthe present invention may be used to assay in vivo variant proteinfunction as well as the activities of a therapeutic agent or compoundthat modulates variant protein function/activity or expression. Suchanimals are also suitable for assessing the effects of null mutations(i.e., mutations that substantially or completely eliminate one or morevariant protein functions).

For further information regarding transgenic animals, see Houdebine,“Antibody manufacture in transgenic animals and comparisons with othersystems,” Curr Opin Biotechnol 13(6):625-9 (December 2002); Petters etal., “Transgenic animals as models for human disease,” Transgenic Res9(4-5):347-51, discussion 345-6 (2000); Wolf et al., “Use of transgenicanimals in understanding molecular mechanisms of toxicity,” J PharmPharmacol 50(6):567-74 (June 1998); Echelard, “Recombinant proteinproduction in transgenic animals,” Curr Opin Biotechnol 7(5):536-40(October 1996); Houdebine, “Transgenic animal bioreactors,” TransgenicRes 9(4-5):305-20 (2000); Pirity et al., “Embryonic stem cells, creatingtransgenic animals,” Methods Cell Biol 57:279-93 (1998); and Robl etal., “Artificial chromosome vectors and expression of complex proteinsin transgenic animals,” Theriogenology 59(1):107-13 (January 2003).

EXAMPLES

The following examples are offered to illustrate, but not limit, theclaimed invention.

Example 1: SNPs Associated with Response to Statins for Reducing VT Risk

27 SNPs were identified that had a significant p(interaction) forstatin*SNP of <0.05 (Wald test) for the statin*SNP interaction term inthe MEGA sample set (ModelFormula: VTE˜SNP+statin user ornonuser+SNP*statin+age+sex). These 27 SNPs are provided in Table 4.Further, Table 6 provides additional SNPs with P(int)<0.1. Thus, theSNPs provided in Tables 4 and 6 can be assayed to determine whetherstatin treatment will reduce an individual's risk for VT.

Analysis of SNPs in Statin Subgroups (Statin Users Vs. Statin Nonusers)

75 SNPs genotyped in MEGA had an additive P<0.05 for VT risk in thestatin nonusers subgroup. Comparing the risk of VT in the statin userssubgroup for these SNPs identifies individuals at risk for VT thatbenefit from statin therapy and individuals at risk for VT that do notbenefit from statin therapy. These 75 SNPs are provided in Table 5.Thus, the SNPs provided in Table 5 can be assayed to determine whetherstatin treatment will reduce an individual's risk for VT.

MEGA Sample Set

The sample sets used in the present analysis were from a largepopulation-based case-control study referred to as the MultipleEnvironmental and Genetic Assessment of risk factors for venousthrombosis (MEGA study) (Koster et al., Lancet 1993;342(8886-8887):1503-1506 and Blom et al., JAMA 2005; 293(6):715-722),including both the MEGA-1 and MEGA-2 subsets of the MEGA study. The MEGAstudy was approved by the Medical Ethics Committee of the LeidenUniversity Medical Center, Leiden, The Netherlands. All participantsgave informed consent to participate.

Collection and ascertainment of VT events in MEGA has been describedpreviously (Blom et al., JAMA 2005; 293(6):715-722; van Stralen et al.,Arch Intern Med 2008; 168(1):21-26). MEGA enrolled consecutive patientsaged 18 to 70 years who presented with their first diagnosis of VT (deepvein thrombosis of the leg, venous thrombosis of the arm, or pulmonaryembolism) at any of six anticoagulation clinics in The Netherlandsbetween Mar. 1, 1999 and May 31, 2004. Control subjects includedpartners of patients and random population control subjectsfrequency-matched on age and sex to the patient group. Participantscompleted a questionnaire on risk factors for VT and medication use(including statins), and provided a blood or buccal swab sample. Sevendifferent statins were used by statin users, which are all combined inthe current analysis, however 94% of statin users used simvastatin,pravastatin, or atorvastatin. The questionnaire included an item onparent birth country as a proxy for ethnicity.

Two SNPs in particular that were identified in MEGA as beingsignificantly associated with statin response for reducing VT risk werein the F11 gene: F11 SNP rs2036914 (see Tables 4 and 5) and F11 SNPrs2289252 (see Table 5).

Example 2: Association of F11 SNPs Rs2036914 and Rs2289252 with Responseto Statin Treatment for Reducing VT Risk

The MEGA study was analyzed to determine whether carriers of the riskalleles of F11 SNPs rs2289252 and rs2036914, compared with noncarriers,were at increased risk for VT among statin users and also amongnonusers.

The MEGA study recruited consecutive patients aged 18 to 70 years with afirst diagnosis of VT (deep vein thrombosis of the leg, venousthrombosis of the arm, or pulmonary embolism) from six anticoagulationclinics in the Netherlands between Mar. 1, 1999 and May 31, 2004 (Blomet al., JAMA. 2005; 293: 715-22). Partners of patients were invited totake part as control participants. Additional controls were recruitedfrom the same geographical region by a random digit dialing method andwere frequency-matched to patients by age and sex (Chinthammitr et al.,J Thromb Haemost. 2006; 4: 2587-92). Information on risk factors for VTand medication use (including statins) prior to their VT event for casesor prior to enrollment for controls was obtained from questionnairescompleted by the participants. Seven different statins were used bystatin users, which are all combined in the current analysis, however94% of statin users used simvastatin, pravastatin, or atorvastatin.Participants also provided a blood or buccal swab sample for DNAextraction. Genotypes were determined in a core laboratory that wasblinded to case-control status (Germer et al., Genome Res. 2000; 10:258-66). All study participants provided written informed consent. TheMEGA study was approved by the Medical Ethics Committee of the LeidenUniversity Medical Center, Leiden, The Netherlands.

DNA was available for 9803 participants. Because active cancer is astrong risk factor for VT that might mask other associations,participants with a known malignancy or missing malignancy status wereexcluded from the current analysis (n=708); participants withoutmedication use information were also excluded (n=204); thus, 3698 caseswith VT and 4473 controls with no history of VT were investigated in thecurrent study. Of these 8171 study participants, 384 (5%) wereself-reported statin users (125 cases and 259 controls). Logisticregression models that adjusted for age and sex were used to assessassociation between genotype and VT in statin users and nonusersseparately using SAS software (version 9.1) (SAS Institute Inc., Cary,N.C., USA).

Cases and controls did not differ appreciably in mean age [cases, 47.2years (standard deviation, 12.9); controls, 47.6 years (standarddeviation, 12.3)] or sex (45.6% of cases and 47.2% of controls weremale). In the controls of MEGA, the genotypes frequencies for rs2289252were 17.1% (TT), 47.1% (TC) and 35.8% (CC) and for rs2036914 were 27.4%(CC), 49.3% (CT) and 23.3% (TT). Genotype distributions for the 2 SNPsin MEGA did not deviate from Hardy-Weinberg expectations among controls(P>0.25) (Weir, Genetic Data Analysis II. Sunderland: Sinauer AssociatesInc., 1996). The linkage disequilibrium between rs2289252 and rs2036914was moderate (r²=0.38) in the HapMap CEPH population (Utah residentswith ancestry from northern and western Europe) (Frazer et al., Nature.2007; 449: 851-61).

Among statin nonusers of MEGA, the rs2289252 and rs2036914 SNPs wereassociated with VT (FIGURE): for participants carrying two risk alleles,compared with those carrying no risk alleles, the OR for VT was 1.83(95% CI, 1.60 to 2.08) for rs2289252 and 1.75 (95% CI, 1.54 to 1.98) forrs2036914. For participants with one risk allele, the OR was 1.39 (95%CI, 1.26 to 1.55) for rs2289252 and 1.30 (95% CI, 1.15 to 1.46) forrs2036914, again compared with participants carrying no risk alleles.

In contrast, among statin users, carriers of rs2289252 were not atincreased risk for VT. For participants carrying two risk alleles,compared with those carrying no risk alleles, the OR for VT was 1.06(95% CI, 0.66 to 1.71); for those carrying one risk allele the OR was1.10 (95% CI, 0.57 to 2.10); and for carriers of 1 or 2 risk alleles,the OR was 1.07 (95% CI, 0.68 to 1.68). Similarly, among statin users,carriers of two rs2036914 risk alleles were also not at increased riskfor VT: the OR was 1.03 (95% CI, 0.53 to 1.99).

It was also determined whether the association between factor V Leidenand VT differed according to statin use. For factor V Leiden, the ORsfor VT were not appreciably different between statin users and nonusers.Among statin users, for carriers of factor V Leiden, compared withnoncarriers, the OR was 4.94 (95% CI, 2.37 to 10.30) and among nonusersthe OR was 3.64 (95% CI, 3.09 to 4.29).

Thus, among MEGA participants who were statin nonusers, it wasdetermined that carriers compared with noncarriers of the risk allelesof rs2289252 and rs2036914 had an increased risk for VT. In contrast,among statin users, carriers of two risk alleles were not at increasedrisk for VT.

Although anticoagulant therapy reduces the risk for VT events by about80% (Dentali et al., Ann Intern Med. 2007; 146: 278-88), anticoagulanttherapy also causes life-threatening bleeding events (Shireman et al.,Chest. 2006; 130: 1390-6; Wittkowsky et al., Arch Intern Med. 2005; 165:703; and Buresly et al., Arch Intern Med. 2005; 165: 784-9). Thus,statin therapy may be a useful treatment option, particularly when thereare concerns about bleeding risk or when the risk of VT is modest. Thegenetic risk for VT from F11 SNPs rs2036914 and rs2289252 exposespatients to a modest lifelong increase in risk for VT, and in this studyof MEGA, the risk for VT in carriers of two alleles of the F11 variantswas attenuated by statin use.

Thus, in conclusion, the association of each of F11 SNPs rs2036914 andrs2289252 with statin response for reducing VT risk in MEGA is shown inthe FIGURE. The FIGURE shows risk of VT according to statin use forrs2289252, rs2036914, and Factor V Leiden genotypes. The odds ratios inthe FIGURE (shown with 95% confidence intervals) were adjusted for sexand age.

As shown in the FIGURE, individuals who were T/T homozygotes or T/Cheterozygotes at F11 SNP rs2289252 and who used statins had a reducedrisk for VT relative to individuals of the same genotype who did not usestatins (lower odds ratios of 1.06 for statin users vs. 1.83 for statinnonusers for T/T homozygous individuals, and lower odds ratio of 1.10for statin users vs. 1.39 for statin nonusers for T/C heterozygousindividuals).

The FIGURE also shows that individuals who were C/C homozygotes at F11SNP rs2036914 and who used statins had a reduced risk for VT relative toindividuals of the same genotype who did not use statins (lower oddsratio of 1.03 for statin users vs. 1.75 for statin nonusers for C/Chomozygous individuals).

Factor XI Protein Levels

In addition to being associated with VT risk, F11 SNPs rs2036914 andrs2289252 are also associated with factor XI protein levels, andincreased factor XI protein levels are associated with increased VT risk(although F11 SNPs rs2036914 and rs2289252 are associated with factor XIprotein levels, both SNPs remain significantly associated with VT riskafter adjustment for factor XI levels). Since increased factor XIprotein levels are associated with increased VT risk, statin therapy mayreduce VT risk by inhibiting factor XI levels associated with the riskalleles of F11 SNPs rs2036914 and rs2289252, or by inhibiting themechanism by which elevated factor XI levels increase VT risk.

Accordingly, in certain exemplary embodiments, a genetic test thatassays one or both of F11 SNPs rs2036914 or rs2289252 (or one or moreother SNPs in high LD with either of these F11 SNP) is used inconjunction with a test that measures factor XI protein levels (e.g., inserum or plasma) to identify patients who will have a greater likelihoodof VT event reduction (i.e., reduced VT risk) from statin therapy (i.e.,increased statin benefit). In further embodiments, a test that measuresfactor XI protein levels can be used in combination with a genetic testthat assays any of the SNPs disclosed herein for VT risk and/or responseto statin treatment for reducing VT risk.

Example 3: Additional Analysis of SNPs Associated with Response toStatins for Reducing VT Risk

Table 7 provides the results from an additional analysis for SNPsassociated with response to statins for reducing risk of VT. Table 7provides SNPs that were significantly associated with response tostatins for reducing risk of VT in the MEGA substudy of statin users.

In this Example, the MEGA study was analyzed to determine whethercertain genotypes of SNPs were at increased risk for VT among statinusers and also among statin nonusers. The MEGA study is described abovein Examples 1 and 2. In the additional analysis described here inExample 3, the results of which are provided in Table 7, a subset ofcontrols were randomly selected rather that using all controls (allcases were used) from MEGA, since controls greatly outnumbered cases inMEGA.

Description of Statin Substudy of MEGA

DNA was available for 9803 participants. Because active cancer is astrong risk factor for VT that might mask other associations,participants with a known malignancy or missing malignancy status wereexcluded from the current analysis (n=708); participants withoutmedication use information were also excluded (n=204); thus, 3698 caseswith VT and 4473 controls with no history of VT were investigated in thecurrent study. Of the 3698 cases with VT, 125 cases were self-reportedstatin users and, of the 4473 controls, 257 were self-reported statinusers. Because only 384 (5%) of the total cohort were statin users, 539cases and 607 controls were randomly selected from among the statinnonusers to genotype and use in the analysis. Logistic regression modelsthat adjusted for age and sex were used to assess association betweengenotype and VT in statin users and nonusers separately using SASsoftware (section of Table 7 labeled “Statin response by genotypegroup”). The association between genotype and VT was assessed in statinusers (section of Table 7 labeled “Risk of VT in statin use group”) andnonusers (section of Table 7 labeled “Risk of VT in no statin usegroup”) separately using regression models that adjusted for age and sexusing SAS software (version 9.1) (SAS Institute Inc., Cary, N.C., USA).

Example 4: SNPs Associated with Risk for VT, Particularly Recurrent VT

An analysis was carried out to identify SNPs associated with VT,particularly recurrent VT. These SNPs are provided in Table 8.Specifically, Table 8 provides 33 SNPs associated with VT risk in a MEGAcase-control study and also with recurrent VT risk in a MEGA recurrentVT prospective study. The MEGA study/sample set is described above inExamples 1 and 2.

Study Design

Recurrent VT Study

The effect of genetic variants on the risk of recurrent VT in MEGA wasassessed. Patients that had a primary VT (either DVT of the leg, PE, orboth) were included in the current study; patients with DVT of the armonly were excluded from the study (Flinterman et al., “Recurrentthrombosis and survival after a first venous thrombosis of the upperextremity”, Circulation. 2008; 118: 1366-72). Since active cancer is arisk factor for VT, participants were excluded who had malignancy or whohad an unknown malignancy status at baseline of the original MEGA study(no information regarding cancer was available during the follow-upstudy of recurrent VT). 3,824 patients with a first VT from the MEGAstudy were followed for recurrent VT events over a mean of five years.Among these patients, 137 patients were lost to follow-up and excludedfrom the analysis. Of these 3,686 participants included in the currentstudy, 565 had a recurrent VT (Table 10).

Primary VT Study

The MEGA primary VT study included 3824 cases and 4672 controls (Table10). Individuals with a history of malignant disorders were excluded.

TABLE 10 Characteristics of cases and controls in MEGA Primary VTRecurrent VT Characteristic Case Control p Value Event No Event p ValueNumber of patients 3824 4672 565 3121 Men 1734 2203 0.11 366 1293<0.0001 Mean age (SD) in yrs 48 (13) 48 (12) 0.98 50 (13) 47 (13)<0.0001

Examination and Laboratory Measures

Data collection methods for the recurrent VT study are described inFlinterman et al. (“Recurrent thrombosis and survival after a firstvenous thrombosis of the upper extremity”, Circulation. 2008; 118:1366-72). Briefly, in 2006, an inquiry form was sent to those patientswho had a primary VT and who had initially agreed to participate in afollow-up study. The patients were asked if they had had another VTevent in any location since their primary VT event and were asked toanswer a follow-up questionnaire. Recurrences were included whenconfirmed by ultrasound, contrast venography, or computed tomographyaccording to the discharge letters (Flinterman et al., “Recurrentthrombosis and survival after a first venous thrombosis of the upperextremity”, Circulation. 2008; 118: 1366-72). Information on patientswith active cancer at the time of first VT was obtained from thebaseline questionnaire and from the discharge letters of the first VT(Blom et al., “Malignancies, prothrombotic mutations, and the risk ofvenous thrombosis”, JAMA. 2005; 293: 715-22).

Genetic Analysis

Blood samples were taken at least three months after discontinuation ofvitamin K antagonist treatment for the first thrombotic event. DNA wascollected with buccal swabs from patients who were unable to give ablood sample and from all patients who were included beginning in June2002 (Blom et al., “Malignancies, prothrombotic mutations, and the riskof venous thrombosis”, JAMA. 2005; 293: 715-22). SNP genotypes weredetermined by allele-specific real-time PCR (Germer et al.,“High-throughput SNP allele-frequency determination in pooled DNAsamples by kinetic PCR”, Genome Res. 2000; 10: 258-66) in a corelaboratory; genotype distributions did not deviate from Hardy Weinbergexpectations among controls (P_(exact)>0.01) (Weir, Genetic DataAnalysis II. Sunderland: Sinauer Associates Inc., 1996).

Statistical Analysis

Recurrent VT Analysis

Cumulative incidence was estimated by the Kaplan-Meier technique.Incidence rates were the number of new VT events over the total numberof person-years. Person-years were calculated from date of first VTevent and from discontinuation of the initial vitamin K antagonisttreatment until recurrent VT event, death, or end of study, whichevercame first. Participants who died during follow-up of a cause other thanVT were censored at the date of death. Patients who were not able tocomplete the inquiry form were censored at their last contact andconsidered study withdrawals. The end-of-study date was Oct. 1, 2006.Hazard ratios (HRs) were estimated with a Cox proportional-hazards modelafter patients had discontinued vitamin K antagonist treatment.Adjustments were made for age and sex. No adjustment was made for racebecause the follow-up study included 95% whites. False discovery rateestimates were used to control for false-positive associations among thegroup of SNPs in the recurrent VT study (Benjamini et al., Journal ofthe Royal Statistical Society. 1995; Serials B: 1289-300). Analyses weredone using SAS version 9 (SAS Institute Inc, Cary, N.C.) and SPSS forWindows, 14.0.2 (SPSS Inc, Chicago, Ill.). False discovery rates wereestimated using the 2-sided, unadjusted P value from the additive model.

Primary VT Analysis

Logistic regression models were used to calculate the odds ratio (OR),95% confidence interval (95% CI), and 2-sided P value for theassociation of each SNP with VT and to adjust for age and sex. For eachSNP, the OR per genotype was calculated relative to noncarriers of therisk allele. For SNPs on the X chromosome, the analysis was conductedseparately in men and women. Analyses were done using SAS version 9 (SASInstitute Inc, Cary, N.C.) and SPSS for Windows, 14.0.2 (SPSS Inc,Chicago, Ill.).

Results

The SNPs identified as being associated with VT, particularly recurrentVT, are provided in Table 8.

Example 5: SNPs Associated with Risk for VT

Table 9 provides 10 SNPs that were associated with VT risk in the MEGA-1subset of the MEGA study. These SNPs were specifically associated withprimary VT risk in MEGA-1, and are also useful for determining risk forrecurrent VT.

The MEGA study, including the MEGA-1 subset, is described in Blom etal., JAMA 2005; 293(6):715-722 (incorporated herein by reference in itsentirety), as well as in Examples 1 and 2 above.

Example 6: Four-Marker Panel for Determining Risk of VT, ParticularlyRecurrent VT

Four of the SNPs identified herein as being associated with recurrentVT, as well as primary VT, were combined into a panel for determining VTrisk, particularly recurrent VT risk. The panel (referred to herein asthe “four-marker panel”, or “GRS” in Tables 11-12) comprised thefollowing four SNPs (genes): rs6025 (F5), rs2066865 (FGG), rs8176719(ABO), and rs2036914 (F11).

Risk genotypes for each of these four SNPs are AG+AA for rs6025 (F5),GT+GG for rs8176719 (ABO), AG+AA for rs2066865 (FGG), and CT+CC forrs2036914 (F11).

Equally weighting these four SNPs, it was found that the individuals inthe top quartile (>90^(th) percentile) had a two-fold increase (HR=2.04)in risk for recurrent VT compared with the bottom quartile group (<35thpercentile) (see Table 11).

TABLE 11 Association of four-marker panel with recurrent VT GRSPercentile Events Total HR 95% CI P value >=90 81 361 2.04 1.56-2.67<0.0001 >35 and <90 326 1998 1.42 1.18-1.72 0.0003 <=35 158 1327 Ref

Percentile >=90: Above 90th percentile (based on number of risk allelecarriers)

Further, using the four-marker panel in combination with an individual'sgender, it was found that individuals in the top quartile (>84thpercentile) had a three-fold increase (HR=3.1) in risk for recurrent VTcompared with the bottom quartile group (<43th percentile) (see Table12).

TABLE 12 Association of four-marker panel, in combination with gender,with recurrent VT GRS Percentile Events Total HR 95% CI P value >=84 155575 3.1 2.47-3.91 <0.0001 >43 and <84 267 1523 2.05 2.05-1.67 <0.0001<=43 143 1588 Ref

Thus, this four-marker panel is particularly useful for determining anindividual's risk for developing VT, particularly recurrent VT (as wellas primary VT).

In further exemplary embodiments of the four-marker panel, additionalmarkers are assayed in combination with the four markers (particularlyadditional markers selected from those disclosed herein). In furtherexemplary embodiments of the four-marker panel, any one, two, or threeof the four markers (F5 SNP rs6025, FGG SNP rs2066865, ABO rs8176719,and F11 SNP rs2036914) are assayed, optionally in combination withadditional markers (particularly additional markers selected from thosedisclosed herein). For example, other markers can be substituted for anyone or more markers of the four-marker panel. In certain exemplaryembodiments, one or more other SNPs in the F11 gene (such as SNPrs2289252) are substituted for F11 SNP rs2036914 (or assayed in additionto rs2036914). In certain embodiments, PTPN21 SNP rs2274736 (disclosedherein) is added to the four-marker panel or substituted in place of oneof the markers of the four-marker panel. Additionally, in certainembodiments, F2 SNP rs1799963 is added to the four-marker panel orsubstituted in place of one of the markers of the four-marker panel.

In additional embodiments, one or more protein biomarkers can be assayedin combination with the four-marker panel, or a subset of thefour-marker panel (and/or any of the other SNPs disclosed herein). Forexample, measurement of factor XI protein levels can be assayed incombination with the four-marker panel, or can be substituted in placeof assaying F11 SNP rs2036914 (or F11 SNP rs2289252), or can be measuredin conjunction with any of the other SNPs disclosed herein.

Similarly, measurement of factor VIII protein levels can be assayed incombination with the four-marker panel or can be substituted in place ofassaying ABO SNP rs8176719 (or can be measured in conjunction with anyof the other SNPs disclosed herein). ABO SNP rs8176719 is associatedwith factor VIII protein levels, and factor VIII protein levels areassociated with VT risk.

Fibrinogen gamma and/or fibrinogen gamma primer protein levels can alsobe measured in conjunction with the four-marker panel or a subsetthereof (or can be measured in conjunction with any of the other SNPsdisclosed herein).

Example 7: LD SNPs Associated with VT Risk and Statin Response

Another investigation was conducted to identify additional SNPs that arecalculated to be in linkage disequilibrium (LD) with certain“interrogated SNPs” that have been found to be associated with VT riskand/or response to statin treatment (particularly for reducing the riskof VT), as described herein and shown in the tables. The interrogatedSNPs are shown in column 1 (which indicates the hCV identificationnumbers of each interrogated SNP) and column 2 (which indicates thepublic rs identification numbers of each interrogated SNP) of Table 3.The methodology is described earlier in the instant application. Tosummarize briefly, the power threshold (T) was set at an appropriatelevel, such as 51%, for detecting disease association using LD markers.This power threshold is based on equation (31) above, which incorporatesallele frequency data from previous disease association studies, thepredicted error rate for not detecting truly disease-associated markers,and a significance level of 0.05. Using this power calculation and thesample size, a threshold level of LD, or r² value, was derived for eachinterrogated SNP (r_(T) ², equations (32) and (33) above). The thresholdr_(T) ² value is the minimum value of linkage disequilibrium between theinterrogated SNP and its LD SNPs possible such that the non-interrogatedSNP still retains a power greater or equal to T for detecting diseaseassociation.

Based on the above methodology, LD SNPs were found for the interrogatedSNPs. Several exemplary LD SNPs for the interrogated SNPs are listed inTable 3; each LD SNP is associated with its respective interrogated SNP.Also shown are the public SNP IDs (rs numbers) for the interrogated andLD SNPs, when available, and the threshold r² value and the power usedto determine this, and the r² value of linkage disequilibrium betweenthe interrogated SNP and its corresponding LD SNP. As an example inTable 3, the interrogated SNP rs2066865 (hCV11503414) was calculated tobe in LD with rs2066864 (hCV11503416) at an r² value of 1, based on a51% power calculation, thus establishing the latter SNP as a markerassociated with statin response as well.

In general, the threshold r_(T) ² value can be set such that one ofordinary skill in the art would consider that any two SNPs having an r²value greater than or equal to the threshold r_(T) ² value would be insufficient LD with each other such that either SNP is useful for thesame utilities, such as determining an individual's response to statintreatment. For example, in various embodiments, the threshold r_(T) ²value used to classify SNPs as being in sufficient LD with aninterrogated SNP (such that these LD SNPs can be used for the sameutilities as the interrogated SNP, for example) can be set at, forexample, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 0.96, 0.97, 0.98, 0.99, 1,etc. (or any other r² value in-between these values). Threshold r_(T) ²values may be utilized with or without considering power or othercalculations.

All publications and patents cited in this specification are hereinincorporated by reference in their entirety. Modifications andvariations of the described compositions, methods and systems of theinvention will be apparent to those skilled in the art without departingfrom the scope and spirit of the invention. Although the invention hasbeen described in connection with specific preferred embodiments andcertain working examples, it should be understood that the invention asclaimed should not be unduly limited to such specific embodiments.Indeed, various modifications of the above-described modes for carryingout the invention that are obvious to those skilled in the field ofmolecular biology, genetics and related fields are intended to be withinthe scope of the following claims.

TABLE 3 Interrogated SNP Interrogated rs LD SNP LD SNP rs PowerThreshold r² r² hCV11503414 rs2066865 hCV11281035 rs4583739 0.510.048174697 0.0695 hCV11503414 rs2066865 hCV11503378 rs1490655 0.510.048174697 0.0612 hCV11503414 rs2066865 hCV11503379 rs1490654 0.510.048174697 0.0677 hCV11503414 rs2066865 hCV11503382 rs1873369 0.510.048174697 0.257 hCV11503414 rs2066865 hCV11503416 rs2066864 0.510.048174697 1 hCV11503414 rs2066865 hCV11503431 rs2066861 0.510.048174697 1 hCV11503414 rs2066865 hCV11503469 rs2066854 0.510.048174697 0.9559 hCV11503414 rs2066865 hCV11503470 rs1800788 0.510.048174697 0.4341 hCV11503414 rs2066865 hCV11852898 rs6819508 0.510.048174697 0.0566 hCV11503414 rs2066865 hCV11853353 rs9995943 0.510.048174697 0.0864 hCV11503414 rs2066865 hCV11853354 rs10030235 0.510.048174697 0.0832 hCV11503414 rs2066865 hCV11853357 rs10033383 0.510.048174697 0.1091 hCV11503414 rs2066865 hCV11853358 rs10000511 0.510.048174697 0.0909 hCV11503414 rs2066865 hCV11853362 rs4696572 0.510.048174697 0.1012 hCV11503414 rs2066865 hCV11853363 rs4696573 0.510.048174697 0.0905 hCV11503414 rs2066865 hCV11853373 rs1907155 0.510.048174697 0.0947 hCV11503414 rs2066865 hCV11853378 rs1907154 0.510.048174697 0.163 hCV11503414 rs2066865 hCV11853384 rs12646456 0.510.048174697 0.163 hCV11503414 rs2066865 hCV11853387 rs1490683 0.510.048174697 0.217 hCV11503414 rs2066865 hCV11853415 rs1490653 0.510.048174697 0.0593 hCV11503414 rs2066865 hCV11853416 rs4346631 0.510.048174697 0.0664 hCV11503414 rs2066865 hCV11853418 rs12501998 0.510.048174697 0.0542 hCV11503414 rs2066865 hCV11853419 rs13151559 0.510.048174697 0.0542 hCV11503414 rs2066865 hCV11853423 rs3857093 0.510.048174697 0.0542 hCV11503414 rs2066865 hCV11853424 rs871541 0.510.048174697 0.0542 hCV11503414 rs2066865 hCV11853483 rs12644950 0.510.048174697 1 hCV11503414 rs2066865 hCV11853489 rs7681423 0.510.048174697 1 hCV11503414 rs2066865 hCV11853496 rs7654093 0.510.048174697 1 hCV11503414 rs2066865 hCV11853631 rs12651106 0.510.048174697 0.1612 hCV11503414 rs2066865 hCV11853650 rs9307922 0.510.048174697 0.1074 hCV11503414 rs2066865 hCV1190562 rs1490684 0.510.048174697 0.0947 hCV11503414 rs2066865 hCV1190563 rs4696565 0.510.048174697 0.114 hCV11503414 rs2066865 hCV1190567 rs4696210 0.510.048174697 0.114 hCV11503414 rs2066865 hCV1190572 rs1032335 0.510.048174697 0.163 hCV11503414 rs2066865 hCV1190580 rs9998926 0.510.048174697 0.0874 hCV11503414 rs2066865 hCV1190581 rs6856249 0.510.048174697 0.114 hCV11503414 rs2066865 hCV1190582 rs10013533 0.510.048174697 0.114 hCV11503414 rs2066865 hCV15860433 rs2070006 0.510.048174697 0.4534 hCV11503414 rs2066865 hCV176753 rs2404478 0.510.048174697 0.0542 hCV11503414 rs2066865 hCV21680 rs7666020 0.510.048174697 0.153 hCV11503414 rs2066865 hCV21681 rs6536018 0.510.048174697 0.3185 hCV11503414 rs2066865 hCV22273499 rs7668014 0.510.048174697 0.0903 hCV11503414 rs2066865 hCV22274180 rs11935584 0.510.048174697 0.1032 hCV11503414 rs2066865 hCV229029 rs13103792 0.510.048174697 0.0486 hCV11503414 rs2066865 hCV2407252 rs149225 0.510.048174697 0.1 hCV11503414 rs2066865 hCV2407354 rs276166 0.510.048174697 0.0534 hCV11503414 rs2066865 hCV24834 rs4235247 0.510.048174697 0.4263 hCV11503414 rs2066865 hCV25610762 rs7668818 0.510.048174697 0.0707 hCV11503414 rs2066865 hCV26019871 rs4547780 0.510.048174697 0.3146 hCV11503414 rs2066865 hCV26024202 rs11731813 0.510.048174697 0.2237 hCV11503414 rs2066865 hCV26024285 rs11726919 0.510.048174697 0.1063 hCV11503414 rs2066865 hCV26024286 rs11726850 0.510.048174697 0.1063 hCV11503414 rs2066865 hCV26024287 rs7666541 0.510.048174697 0.1357 hCV11503414 rs2066865 hCV26024294 rs11731663 0.510.048174697 0.1063 hCV11503414 rs2066865 hCV265748 rs12500118 0.510.048174697 0.1669 hCV11503414 rs2066865 hCV27020269 rs7659613 0.510.048174697 0.5249 hCV11503414 rs2066865 hCV27020277 rs6825454 0.510.048174697 0.8713 hCV11503414 rs2066865 hCV27020280 rs4463047 0.510.048174697 0.2252 hCV11503414 rs2066865 hCV27020304 rs13101534 0.510.048174697 0.1091 hCV11503414 rs2066865 hCV27313130 rs4634202 0.510.048174697 0.103 hCV11503414 rs2066865 hCV27479909 rs3775785 0.510.048174697 0.1072 hCV11503414 rs2066865 hCV27905214 rs4323084 0.510.048174697 0.2956 hCV11503414 rs2066865 hCV27907560 rs4696576 0.510.048174697 0.135 hCV11503414 rs2066865 hCV27937396 rs4634201 0.510.048174697 0.4298 hCV11503414 rs2066865 hCV286004 rs1118824 0.510.048174697 0.1213 hCV11503414 rs2066865 hCV2891425 rs1948714 0.510.048174697 0.1065 hCV11503414 rs2066865 hCV2891532 rs13110294 0.510.048174697 0.1006 hCV11503414 rs2066865 hCV2892850 rs10050268 0.510.048174697 0.0552 hCV11503414 rs2066865 hCV2892855 rs6536024 0.510.048174697 0.2222 hCV11503414 rs2066865 hCV2892858 rs12648395 0.510.048174697 0.1213 hCV11503414 rs2066865 hCV2892859 rs13130318 0.510.048174697 0.859 hCV11503414 rs2066865 hCV2892863 rs1049636 0.510.048174697 0.1213 hCV11503414 rs2066865 hCV2892869 rs13109457 0.510.048174697 0.955 hCV11503414 rs2066865 hCV2892870 rs2070011 0.510.048174697 0.439 hCV11503414 rs2066865 hCV2892876 rs2070018 0.510.048174697 0.0566 hCV11503414 rs2066865 hCV2892877 rs6050 0.510.048174697 0.873 hCV11503414 rs2066865 hCV2892893 rs12648258 0.510.048174697 0.4009 hCV11503414 rs2066865 hCV2892895 rs12641958 0.510.048174697 0.0903 hCV11503414 rs2066865 hCV2892896 rs11940724 0.510.048174697 0.0903 hCV11503414 rs2066865 hCV2892899 rs7680155 0.510.048174697 0.1032 hCV11503414 rs2066865 hCV2892905 rs12642770 0.510.048174697 0.3619 hCV11503414 rs2066865 hCV2892918 rs12511469 0.510.048174697 0.3888 hCV11503414 rs2066865 hCV2892923 rs13435192 0.510.048174697 0.1113 hCV11503414 rs2066865 hCV2892924 rs13435101 0.510.048174697 0.1105 hCV11503414 rs2066865 hCV2892925 rs7689945 0.510.048174697 0.1063 hCV11503414 rs2066865 hCV2892926 rs7662567 0.510.048174697 0.3986 hCV11503414 rs2066865 hCV2892927 rs13123551 0.510.048174697 0.1327 hCV11503414 rs2066865 hCV2892928 rs13147579 0.510.048174697 0.4128 hCV11503414 rs2066865 hCV28953838 rs7690851 0.510.048174697 0.3221 hCV11503414 rs2066865 hCV28953840 rs6536017 0.510.048174697 0.1155 hCV11503414 rs2066865 hCV28954780 rs7656522 0.510.048174697 0.0537 hCV11503414 rs2066865 hCV28966638 rs7676857 0.510.048174697 0.1625 hCV11503414 rs2066865 hCV29317506 rs7686002 0.510.048174697 0.0551 hCV11503414 rs2066865 hCV29420822 rs4642230 0.510.048174697 0.4837 hCV11503414 rs2066865 hCV29420827 rs7654425 0.510.048174697 0.0903 hCV11503414 rs2066865 hCV29420828 rs7660120 0.510.048174697 0.0796 hCV11503414 rs2066865 hCV29570696 rs9997519 0.510.048174697 0.0523 hCV11503414 rs2066865 hCV29582612 rs4550901 0.510.048174697 0.0566 hCV11503414 rs2066865 hCV29751345 rs6811271 0.510.048174697 0.108 hCV11503414 rs2066865 hCV29983641 rs10008078 0.510.048174697 0.461 hCV11503414 rs2066865 hCV30004073 rs6832957 0.510.048174697 0.049 hCV11503414 rs2066865 hCV30562176 rs9284660 0.510.048174697 0.1006 hCV11503414 rs2066865 hCV30679139 rs13139082 0.510.048174697 0.0593 hCV11503414 rs2066865 hCV30679140 rs13112066 0.510.048174697 0.0499 hCV11503414 rs2066865 hCV30679141 rs13111621 0.510.048174697 0.0629 hCV11503414 rs2066865 hCV30679164 rs12649437 0.510.048174697 0.1051 hCV11503414 rs2066865 hCV30679170 rs13148992 0.510.048174697 0.2324 hCV11503414 rs2066865 hCV30679242 rs4235243 0.510.048174697 0.1248 hCV11503414 rs2066865 hCV30679244 rs4575978 0.510.048174697 0.1063 hCV11503414 rs2066865 hCV30679245 rs4386583 0.510.048174697 0.1063 hCV11503414 rs2066865 hCV30711231 rs12642469 0.510.048174697 0.461 hCV11503414 rs2066865 hCV31863942 rs13101382 0.510.048174697 0.1052 hCV11503414 rs2066865 hCV31863979 rs12186294 0.510.048174697 0.2778 hCV11503414 rs2066865 hCV31863982 rs7659024 0.510.048174697 1 hCV11503414 rs2066865 hCV31863989 rs4308349 0.510.048174697 0.0513 hCV11503414 rs2066865 hCV31863993 rs7673587 0.510.048174697 0.1032 hCV11503414 rs2066865 hCV32212659 rs4622984 0.510.048174697 0.1879 hCV11503414 rs2066865 hCV32212662 rs11099958 0.510.048174697 0.0527 hCV11503414 rs2066865 hCV32212663 rs7670827 0.510.048174697 0.0974 hCV11503414 rs2066865 hCV32212664 rs12642646 0.510.048174697 0.0491 hCV11503414 rs2066865 hCV32212669 rs12649647 0.510.048174697 0.0577 hCV11503414 rs2066865 hCV354895 rs11737226 0.510.048174697 0.2322 hCV11503414 rs2066865 hCV354896 rs7690972 0.510.048174697 0.2322 hCV11503414 rs2066865 hCV36809 rs10517590 0.510.048174697 0.133 hCV11503414 rs2066865 hCV400532 rs11099956 0.510.048174697 0.1095 hCV11503414 rs2066865 hCV426162 rs10857275 0.510.048174697 0.1132 hCV11503414 rs2066865 hCV426165 rs990185 0.510.048174697 0.1074 hCV11503414 rs2066865 hCV426167 rs1388087 0.510.048174697 0.0905 hCV11503414 rs2066865 hCV426168 rs1388088 0.510.048174697 0.114 hCV11503414 rs2066865 hCV426169 rs1388066 0.510.048174697 0.1336 hCV11503414 rs2066865 hCV426170 rs1388067 0.510.048174697 0.114 hCV11503414 rs2066865 hCV426172 rs7670027 0.510.048174697 0.1443 hCV11503414 rs2066865 hCV426173 rs12504201 0.510.048174697 0.2207 hCV11503414 rs2066865 hCV426175 rs9884952 0.510.048174697 0.163 hCV11503414 rs2066865 hCV426176 rs9884775 0.510.048174697 0.163 hCV11503414 rs2066865 hCV426178 rs9884570 0.510.048174697 0.1519 hCV11503414 rs2066865 hCV426181 rs11099955 0.510.048174697 0.163 hCV11503414 rs2066865 hCV426182 rs10014536 0.510.048174697 0.1769 hCV11503414 rs2066865 hCV426183 rs10014635 0.510.048174697 0.1772 hCV11503414 rs2066865 hCV426184 rs1032336 0.510.048174697 0.163 hCV11503414 rs2066865 hCV437164 rs7685964 0.510.048174697 0.1071 hCV11503414 rs2066865 hCV470979 rs1490672 0.510.048174697 0.2211 hCV11503414 rs2066865 hCV501682 rs4403033 0.510.048174697 0.1063 hCV11503414 rs2066865 hCV501683 rs4312742 0.510.048174697 0.1248 hCV11503414 rs2066865 hCV501686 rs4327464 0.510.048174697 0.1026 hCV11503414 rs2066865 hCV7429674 rs871540 0.510.048174697 0.0542 hCV11503414 rs2066865 hCV7429780 rs1800792 0.510.048174697 0.2745 hCV11503414 rs2066865 hCV7429782 rs1118823 0.510.048174697 0.1185 hCV11503414 rs2066865 hCV7429783 rs1044291 0.510.048174697 0.0903 hCV11503414 rs2066865 hCV7429793 rs1025154 0.510.048174697 0.461 hCV11503414 rs2066865 hCV7430148 rs1490685 0.510.048174697 0.163 hCV11503414 rs2066865 hCV7430149 rs1490649 0.510.048174697 0.1131 hCV11503414 rs2066865 hCV7430150 rs1490648 0.510.048174697 0.1182 hCV11503414 rs2066865 hCV7430152 rs1490656 0.510.048174697 0.1029 hCV11503414 rs2066865 hCV7430153 rs1388077 0.510.048174697 0.114 hCV11503414 rs2066865 hCV7430158 rs1466662 0.510.048174697 0.1669 hCV11503414 rs2066865 hCV8938834 rs1500372 0.510.048174697 0.076 hCV11503414 rs2066865 hCV8938838 rs1392546 0.510.048174697 0.076 hCV11503414 rs2066865 hCV9317142 rs12186175 0.510.048174697 0.1052 hCV11503414 rs2066865 hCV99436 rs10015747 0.510.048174697 0.1308 hCV11503414 rs2066865 hDV70934991 rs17301943 0.510.048174697 0.0542 hCV11503414 rs2066865 hDV70945235 rs17373860 0.510.048174697 0.16 hCV11503414 rs2066865 hDV77232287 rs7666918 0.510.048174697 0.0903 hCV11503414 rs2066865 hDV96226316 rs6834312 0.510.048174697 0.1334 hCV11503469 rs2066854 hCV11281035 rs4583739 0.510.048166678 0.094 hCV11503469 rs2066854 hCV11503378 rs1490655 0.510.048166678 0.068 hCV11503469 rs2066854 hCV11503379 rs1490654 0.510.048166678 0.0512 hCV11503469 rs2066854 hCV11503382 rs1873369 0.510.048166678 0.1718 hCV11503469 rs2066854 hCV11503414 rs2066865 0.510.048166678 0.9559 hCV11503469 rs2066854 hCV11503416 rs2066864 0.510.048166678 0.9579 hCV11503469 rs2066854 hCV11503431 rs2066861 0.510.048166678 0.9559 hCV11503469 rs2066854 hCV11503470 rs1800788 0.510.048166678 0.3765 hCV11503469 rs2066854 hCV11853342 rs7660343 0.510.048166678 0.0674 hCV11503469 rs2066854 hCV11853353 rs9995943 0.510.048166678 0.0981 hCV11503469 rs2066854 hCV11853354 rs10030235 0.510.048166678 0.0868 hCV11503469 rs2066854 hCV11853357 rs10033383 0.510.048166678 0.0595 hCV11503469 rs2066854 hCV11853362 rs4696572 0.510.048166678 0.1483 hCV11503469 rs2066854 hCV11853363 rs4696573 0.510.048166678 0.0981 hCV11503469 rs2066854 hCV11853373 rs1907155 0.510.048166678 0.1398 hCV11503469 rs2066854 hCV11853378 rs1907154 0.510.048166678 0.0869 hCV11503469 rs2066854 hCV11853384 rs12646456 0.510.048166678 0.0869 hCV11503469 rs2066854 hCV11853387 rs1490683 0.510.048166678 0.1451 hCV11503469 rs2066854 hCV11853416 rs4346631 0.510.048166678 0.05 hCV11503469 rs2066854 hCV11853418 rs12501998 0.510.048166678 0.0786 hCV11503469 rs2066854 hCV11853419 rs13151559 0.510.048166678 0.0786 hCV11503469 rs2066854 hCV11853423 rs3857093 0.510.048166678 0.0786 hCV11503469 rs2066854 hCV11853424 rs871541 0.510.048166678 0.0786 hCV11503469 rs2066854 hCV11853483 rs12644950 0.510.048166678 0.9545 hCV11503469 rs2066854 hCV11853489 rs7681423 0.510.048166678 0.9579 hCV11503469 rs2066854 hCV11853496 rs7654093 0.510.048166678 0.9559 hCV11503469 rs2066854 hCV11853631 rs12651106 0.510.048166678 0.1768 hCV11503469 rs2066854 hCV1190562 rs1490684 0.510.048166678 0.1398 hCV11503469 rs2066854 hCV1190563 rs4696565 0.510.048166678 0.063 hCV11503469 rs2066854 hCV1190567 rs4696210 0.510.048166678 0.063 hCV11503469 rs2066854 hCV1190572 rs1032335 0.510.048166678 0.0869 hCV11503469 rs2066854 hCV1190580 rs9998926 0.510.048166678 0.0915 hCV11503469 rs2066854 hCV1190581 rs6856249 0.510.048166678 0.063 hCV11503469 rs2066854 hCV1190582 rs10013533 0.510.048166678 0.063 hCV11503469 rs2066854 hCV15860433 rs2070006 0.510.048166678 0.5293 hCV11503469 rs2066854 hCV15971616 rs2227421 0.510.048166678 0.1143 hCV11503469 rs2066854 hCV176753 rs2404478 0.510.048166678 0.0786 hCV11503469 rs2066854 hCV21680 rs7666020 0.510.048166678 0.1247 hCV11503469 rs2066854 hCV21681 rs6536018 0.510.048166678 0.2928 hCV11503469 rs2066854 hCV22273499 rs7668014 0.510.048166678 0.1071 hCV11503469 rs2066854 hCV22274180 rs11935584 0.510.048166678 0.1125 hCV11503469 rs2066854 hCV229029 rs13103792 0.510.048166678 0.062 hCV11503469 rs2066854 hCV2407223 rs156502 0.510.048166678 0.0621 hCV11503469 rs2066854 hCV2407232 rs156550 0.510.048166678 0.0563 hCV11503469 rs2066854 hCV2407238 rs156543 0.510.048166678 0.0615 hCV11503469 rs2066854 hCV2407252 rs149225 0.510.048166678 0.105 hCV11503469 rs2066854 hCV24834 rs4235247 0.510.048166678 0.4128 hCV11503469 rs2066854 hCV25610762 rs7668818 0.510.048166678 0.0634 hCV11503469 rs2066854 hCV26019871 rs4547780 0.510.048166678 0.3094 hCV11503469 rs2066854 hCV26024202 rs11731813 0.510.048166678 0.225 hCV11503469 rs2066854 hCV26024287 rs7666541 0.510.048166678 0.1353 hCV11503469 rs2066854 hCV26024295 rs12643125 0.510.048166678 0.1125 hCV11503469 rs2066854 hCV265748 rs12500118 0.510.048166678 0.1103 hCV11503469 rs2066854 hCV27020184 rs47379 0.510.048166678 0.0776 hCV11503469 rs2066854 hCV27020269 rs7659613 0.510.048166678 0.5455 hCV11503469 rs2066854 hCV27020277 rs6825454 0.510.048166678 0.8694 hCV11503469 rs2066854 hCV27020280 rs4463047 0.510.048166678 0.2409 hCV11503469 rs2066854 hCV27020284 rs1846707 0.510.048166678 0.1139 hCV11503469 rs2066854 hCV27313130 rs4634202 0.510.048166678 0.1555 hCV11503469 rs2066854 hCV27479909 rs3775785 0.510.048166678 0.0578 hCV11503469 rs2066854 hCV27905214 rs4323084 0.510.048166678 0.325 hCV11503469 rs2066854 hCV27907560 rs4696576 0.510.048166678 0.0999 hCV11503469 rs2066854 hCV27937396 rs4634201 0.510.048166678 0.4472 hCV11503469 rs2066854 hCV286004 rs1118824 0.510.048166678 0.1531 hCV11503469 rs2066854 hCV2891496 rs156584 0.510.048166678 0.0621 hCV11503469 rs2066854 hCV2891515 rs11940892 0.510.048166678 0.0615 hCV11503469 rs2066854 hCV2891530 rs7662464 0.510.048166678 0.0615 hCV11503469 rs2066854 hCV2891532 rs13110294 0.510.048166678 0.0626 hCV11503469 rs2066854 hCV2891552 rs1876031 0.510.048166678 0.1011 hCV11503469 rs2066854 hCV2891554 rs12501328 0.510.048166678 0.059 hCV11503469 rs2066854 hCV2892850 rs10050268 0.510.048166678 0.0638 hCV11503469 rs2066854 hCV2892855 rs6536024 0.510.048166678 0.2667 hCV11503469 rs2066854 hCV2892858 rs12648395 0.510.048166678 0.1531 hCV11503469 rs2066854 hCV2892859 rs13130318 0.510.048166678 0.8253 hCV11503469 rs2066854 hCV2892863 rs1049636 0.510.048166678 0.1531 hCV11503469 rs2066854 hCV2892869 rs13109457 0.510.048166678 0.9149 hCV11503469 rs2066854 hCV2892870 rs2070011 0.510.048166678 0.5068 hCV11503469 rs2066854 hCV2892877 rs6050 0.510.048166678 0.8287 hCV11503469 rs2066854 hCV2892878 rs2070022 0.510.048166678 0.0592 hCV11503469 rs2066854 hCV2892889 rs2227412 0.510.048166678 0.0547 hCV11503469 rs2066854 hCV2892893 rs12648258 0.510.048166678 0.4044 hCV11503469 rs2066854 hCV2892895 rs12641958 0.510.048166678 0.1071 hCV11503469 rs2066854 hCV2892896 rs11940724 0.510.048166678 0.1071 hCV11503469 rs2066854 hCV2892899 rs7680155 0.510.048166678 0.1125 hCV11503469 rs2066854 hCV2892905 rs12642770 0.510.048166678 0.3381 hCV11503469 rs2066854 hCV2892918 rs12511469 0.510.048166678 0.3613 hCV11503469 rs2066854 hCV2892923 rs13435192 0.510.048166678 0.1375 hCV11503469 rs2066854 hCV2892924 rs13435101 0.510.048166678 0.1375 hCV11503469 rs2066854 hCV2892925 rs7689945 0.510.048166678 0.1375 hCV11503469 rs2066854 hCV2892926 rs7662567 0.510.048166678 0.3671 hCV11503469 rs2066854 hCV2892927 rs13123551 0.510.048166678 0.1434 hCV11503469 rs2066854 hCV2892928 rs13147579 0.510.048166678 0.3836 hCV11503469 rs2066854 hCV28953838 rs7690851 0.510.048166678 0.3242 hCV11503469 rs2066854 hCV28953840 rs6536017 0.510.048166678 0.1025 hCV11503469 rs2066854 hCV28954780 rs7656522 0.510.048166678 0.0782 hCV11503469 rs2066854 hCV28954790 rs7662783 0.510.048166678 0.0496 hCV11503469 rs2066854 hCV28954801 rs4447837 0.510.048166678 0.062 hCV11503469 rs2066854 hCV28966638 rs7676857 0.510.048166678 0.1179 hCV11503469 rs2066854 hCV29420822 rs4642230 0.510.048166678 0.4022 hCV11503469 rs2066854 hCV29420827 rs7654425 0.510.048166678 0.1071 hCV11503469 rs2066854 hCV29420828 rs7660120 0.510.048166678 0.0906 hCV11503469 rs2066854 hCV29570696 rs9997519 0.510.048166678 0.0519 hCV11503469 rs2066854 hCV29636755 rs10517602 0.510.048166678 0.0706 hCV11503469 rs2066854 hCV29751345 rs6811271 0.510.048166678 0.1681 hCV11503469 rs2066854 hCV29983641 rs10008078 0.510.048166678 0.3893 hCV11503469 rs2066854 hCV30562176 rs9284660 0.510.048166678 0.0785 hCV11503469 rs2066854 hCV30679139 rs13139082 0.510.048166678 0.0616 hCV11503469 rs2066854 hCV30679140 rs13112066 0.510.048166678 0.0674 hCV11503469 rs2066854 hCV30679164 rs12649437 0.510.048166678 0.0849 hCV11503469 rs2066854 hCV30679170 rs13148992 0.510.048166678 0.2399 hCV11503469 rs2066854 hCV30711231 rs12642469 0.510.048166678 0.3893 hCV11503469 rs2066854 hCV31863937 rs12507608 0.510.048166678 0.0706 hCV11503469 rs2066854 hCV31863979 rs12186294 0.510.048166678 0.3086 hCV11503469 rs2066854 hCV31863982 rs7659024 0.510.048166678 0.9559 hCV11503469 rs2066854 hCV31863993 rs7673587 0.510.048166678 0.1125 hCV11503469 rs2066854 hCV32212658 rs11099959 0.510.048166678 0.0536 hCV11503469 rs2066854 hCV32212659 rs4622984 0.510.048166678 0.195 hCV11503469 rs2066854 hCV32212663 rs7670827 0.510.048166678 0.1002 hCV11503469 rs2066854 hCV32212664 rs12642646 0.510.048166678 0.0849 hCV11503469 rs2066854 hCV32287640 rs4367156 0.510.048166678 0.062 hCV11503469 rs2066854 hCV354895 rs11737226 0.510.048166678 0.2251 hCV11503469 rs2066854 hCV354896 rs7690972 0.510.048166678 0.2251 hCV11503469 rs2066854 hCV37878 rs4235241 0.510.048166678 0.1157 hCV11503469 rs2066854 hCV400532 rs11099956 0.510.048166678 0.0951 hCV11503469 rs2066854 hCV426167 rs1388087 0.510.048166678 0.0981 hCV11503469 rs2066854 hCV426168 rs1388088 0.510.048166678 0.063 hCV11503469 rs2066854 hCV426169 rs1388066 0.510.048166678 0.0794 hCV11503469 rs2066854 hCV426170 rs1388067 0.510.048166678 0.063 hCV11503469 rs2066854 hCV426172 rs7670027 0.510.048166678 0.083 hCV11503469 rs2066854 hCV426173 rs12504201 0.510.048166678 0.1597 hCV11503469 rs2066854 hCV426175 rs9884952 0.510.048166678 0.0816 hCV11503469 rs2066854 hCV426176 rs9884775 0.510.048166678 0.0869 hCV11503469 rs2066854 hCV426178 rs9884570 0.510.048166678 0.078 hCV11503469 rs2066854 hCV426181 rs11099955 0.510.048166678 0.0869 hCV11503469 rs2066854 hCV426182 rs10014536 0.510.048166678 0.1101 hCV11503469 rs2066854 hCV426183 rs10014635 0.510.048166678 0.0914 hCV11503469 rs2066854 hCV426184 rs1032336 0.510.048166678 0.0869 hCV11503469 rs2066854 hCV437164 rs7685964 0.510.048166678 0.0537 hCV11503469 rs2066854 hCV470979 rs1490672 0.510.048166678 0.2217 hCV11503469 rs2066854 hCV489970 rs11734901 0.510.048166678 0.1235 hCV11503469 rs2066854 hCV501681 rs4076040 0.510.048166678 0.1157 hCV11503469 rs2066854 hCV7429674 rs871540 0.510.048166678 0.0786 hCV11503469 rs2066854 hCV7429780 rs1800792 0.510.048166678 0.3086 hCV11503469 rs2066854 hCV7429782 rs1118823 0.510.048166678 0.1531 hCV11503469 rs2066854 hCV7429783 rs1044291 0.510.048166678 0.1141 hCV11503469 rs2066854 hCV7429793 rs1025154 0.510.048166678 0.3893 hCV11503469 rs2066854 hCV7430148 rs1490685 0.510.048166678 0.0869 hCV11503469 rs2066854 hCV7430149 rs1490649 0.510.048166678 0.0623 hCV11503469 rs2066854 hCV7430150 rs1490648 0.510.048166678 0.0661 hCV11503469 rs2066854 hCV7430152 rs1490656 0.510.048166678 0.0539 hCV11503469 rs2066854 hCV7430153 rs1388077 0.510.048166678 0.063 hCV11503469 rs2066854 hCV7430158 rs1466662 0.510.048166678 0.1103 hCV11503469 rs2066854 hDV70817639 rs17031739 0.510.048166678 0.0603 hCV11503469 rs2066854 hDV70817640 rs17031740 0.510.048166678 0.062 hCV11503469 rs2066854 hDV70817803 rs17031951 0.510.048166678 0.0706 hCV11503469 rs2066854 hDV70817805 rs17031954 0.510.048166678 0.0706 hCV11503469 rs2066854 hDV70817844 rs17032000 0.510.048166678 0.0706 hCV11503469 rs2066854 hDV70934991 rs17301943 0.510.048166678 0.0786 hCV11503469 rs2066854 hDV70945235 rs17373860 0.510.048166678 0.129 hCV11503469 rs2066854 hDV72277158 rs28673871 0.510.048166678 0.0592 hCV11503469 rs2066854 hDV77232287 rs7666918 0.510.048166678 0.1071 hCV11503469 rs2066854 hDV96226316 rs6834312 0.510.048166678 0.0607 hCV11503470 rs1800788 hCV11503382 rs1873369 0.510.150481176 0.5598 hCV11503470 rs1800788 hCV11503414 rs2066865 0.510.150481176 0.4341 hCV11503470 rs1800788 hCV11503416 rs2066864 0.510.150481176 0.4007 hCV11503470 rs1800788 hCV11503431 rs2066861 0.510.150481176 0.4356 hCV11503470 rs1800788 hCV11503469 rs2066854 0.510.150481176 0.3765 hCV11503470 rs1800788 hCV11853483 rs12644950 0.510.150481176 0.3743 hCV11503470 rs1800788 hCV11853489 rs7681423 0.510.150481176 0.4007 hCV11503470 rs1800788 hCV11853496 rs7654093 0.510.150481176 0.4356 hCV11503470 rs1800788 hCV15860433 rs2070006 0.510.150481176 0.2862 hCV11503470 rs1800788 hCV21680 rs7666020 0.510.150481176 0.168 hCV11503470 rs1800788 hCV21681 rs6536018 0.510.150481176 0.2707 hCV11503470 rs1800788 hCV24834 rs4235247 0.510.150481176 0.6801 hCV11503470 rs1800788 hCV26019871 rs4547780 0.510.150481176 0.2046 hCV11503470 rs1800788 hCV26024202 rs11731813 0.510.150481176 0.4748 hCV11503470 rs1800788 hCV27020269 rs7659613 0.510.150481176 0.3134 hCV11503470 rs1800788 hCV27020277 rs6825454 0.510.150481176 0.4968 hCV11503470 rs1800788 hCV27020280 rs4463047 0.510.150481176 0.4485 hCV11503470 rs1800788 hCV27313130 rs4634202 0.510.150481176 0.3826 hCV11503470 rs1800788 hCV27905214 rs4323084 0.510.150481176 0.5288 hCV11503470 rs1800788 hCV27907560 rs4696576 0.510.150481176 0.2691 hCV11503470 rs1800788 hCV27937396 rs4634201 0.510.150481176 0.6797 hCV11503470 rs1800788 hCV2892859 rs13130318 0.510.150481176 0.2782 hCV11503470 rs1800788 hCV2892869 rs13109457 0.510.150481176 0.4255 hCV11503470 rs1800788 hCV2892870 rs2070011 0.510.150481176 0.3019 hCV11503470 rs1800788 hCV2892877 rs6050 0.510.150481176 0.5042 hCV11503470 rs1800788 hCV2892893 rs12648258 0.510.150481176 1 hCV11503470 rs1800788 hCV2892905 rs12642770 0.510.150481176 0.8219 hCV11503470 rs1800788 hCV2892918 rs12511469 0.510.150481176 1 hCV11503470 rs1800788 hCV2892923 rs13435192 0.510.150481176 0.2139 hCV11503470 rs1800788 hCV2892924 rs13435101 0.510.150481176 0.2119 hCV11503470 rs1800788 hCV2892925 rs7689945 0.510.150481176 0.2079 hCV11503470 rs1800788 hCV2892926 rs7662567 0.510.150481176 1 hCV11503470 rs1800788 hCV2892927 rs13123551 0.510.150481176 0.2674 hCV11503470 rs1800788 hCV2892928 rs13147579 0.510.150481176 1 hCV11503470 rs1800788 hCV28953838 rs7690851 0.510.150481176 0.211 hCV11503470 rs1800788 hCV28953840 rs6536017 0.510.150481176 0.1546 hCV11503470 rs1800788 hCV29420822 rs4642230 0.510.150481176 0.9 hCV11503470 rs1800788 hCV29983641 rs10008078 0.510.150481176 0.9719 hCV11503470 rs1800788 hCV30679170 rs13148992 0.510.150481176 0.4826 hCV11503470 rs1800788 hCV30711231 rs12642469 0.510.150481176 0.9719 hCV11503470 rs1800788 hCV31863979 rs12186294 0.510.150481176 0.1637 hCV11503470 rs1800788 hCV31863982 rs7659024 0.510.150481176 0.4356 hCV11503470 rs1800788 hCV32212658 rs11099959 0.510.150481176 0.163 hCV11503470 rs1800788 hCV32212659 rs4622984 0.510.150481176 0.4821 hCV11503470 rs1800788 hCV32212664 rs12642646 0.510.150481176 0.2273 hCV11503470 rs1800788 hCV32212669 rs12649647 0.510.150481176 0.1508 hCV11503470 rs1800788 hCV354895 rs11737226 0.510.150481176 0.5659 hCV11503470 rs1800788 hCV354896 rs7690972 0.510.150481176 0.5659 hCV11503470 rs1800788 hCV470979 rs1490672 0.510.150481176 0.4671 hCV11503470 rs1800788 hCV7429793 rs1025154 0.510.150481176 0.9719 hCV11503470 rs1800788 hDV70945235 rs17373860 0.510.150481176 0.2419 hCV11541681 rs2001490 hCV112099 rs12052539 0.510.847343426 0.9243 hCV11541681 rs2001490 hCV112100 rs17350125 0.510.847343426 0.9268 hCV11541681 rs2001490 hCV11537012 rs12992607 0.510.847343426 0.8544 hCV11541681 rs2001490 hCV11537013 rs12713793 0.510.847343426 0.849 hCV11541681 rs2001490 hCV11541694 rs12619258 0.510.847343426 1 hCV11541681 rs2001490 hCV11541701 rs6748233 0.510.847343426 0.9268 hCV11541681 rs2001490 hCV11541702 rs4852978 0.510.847343426 0.9268 hCV11541681 rs2001490 hCV11541712 rs12713791 0.510.847343426 0.8856 hCV11541681 rs2001490 hCV11541719 rs12615807 0.510.847343426 0.8544 hCV11541681 rs2001490 hCV11541721 rs2006997 0.510.847343426 0.8544 hCV11541681 rs2001490 hCV11941453 rs2001436 0.510.847343426 1 hCV11541681 rs2001490 hCV133926 rs12053242 0.510.847343426 0.9268 hCV11541681 rs2001490 hCV133927 rs7599453 0.510.847343426 0.9237 hCV11541681 rs2001490 hCV133928 rs4852977 0.510.847343426 0.9268 hCV11541681 rs2001490 hCV133930 rs1815028 0.510.847343426 0.9268 hCV11541681 rs2001490 hCV15804221 rs2421674 0.510.847343426 0.849 hCV11541681 rs2001490 hCV15804228 rs2421675 0.510.847343426 0.8544 hCV11541681 rs2001490 hCV180709 rs7591112 0.510.847343426 0.8898 hCV11541681 rs2001490 hCV180710 rs11891140 0.510.847343426 0.8898 hCV11541681 rs2001490 hCV1835582 rs12713789 0.510.847343426 0.8874 hCV11541681 rs2001490 hCV1835584 rs6749841 0.510.847343426 0.8856 hCV11541681 rs2001490 hCV2050088 rs2272178 0.510.847343426 0.8544 hCV11541681 rs2001490 hCV2050091 rs35791379 0.510.847343426 0.849 hCV11541681 rs2001490 hCV2050092 rs12624267 0.510.847343426 0.849 hCV11541681 rs2001490 hCV2050096 rs2116367 0.510.847343426 0.8544 hCV11541681 rs2001490 hCV25924555 rs13003035 0.510.847343426 0.8544 hCV11541681 rs2001490 hCV26996655 rs12713790 0.510.847343426 0.8889 hCV11541681 rs2001490 hCV26996656 rs1806683 0.510.847343426 0.9243 hCV11541681 rs2001490 hCV26996674 rs13006448 0.510.847343426 1 hCV11541681 rs2001490 hCV26996679 rs6732812 0.510.847343426 1 hCV11541681 rs2001490 hCV26996688 rs13015885 0.510.847343426 1 hCV11541681 rs2001490 hCV26996689 rs13014700 0.510.847343426 1 hCV11541681 rs2001490 hCV26996690 rs2421575 0.510.847343426 1 hCV11541681 rs2001490 hCV26996697 rs12611487 0.510.847343426 1 hCV11541681 rs2001490 hCV26996701 rs7608328 0.510.847343426 0.8545 hCV11541681 rs2001490 hCV26996705 rs12997018 0.510.847343426 0.9547 hCV11541681 rs2001490 hCV29307907 rs4852316 0.510.847343426 0.9243 hCV11541681 rs2001490 hCV303807 rs17350188 0.510.847343426 0.849 hCV11541681 rs2001490 hCV31840120 rs12713798 0.510.847343426 0.849 hCV11541681 rs2001490 hCV31840129 rs11126417 0.510.847343426 0.849 hCV11541681 rs2001490 hCV31840132 rs2421676 0.510.847343426 0.849 hCV11541681 rs2001490 hCV31840134 rs11894953 0.510.847343426 0.849 hCV11541681 rs2001490 hCV31840136 rs12713795 0.510.847343426 0.8544 hCV11541681 rs2001490 hCV31840146 rs11126415 0.510.847343426 0.9268 hCV11541681 rs2001490 hCV31840149 rs12233112 0.510.847343426 1 hCV11541681 rs2001490 hCV31840152 rs12998980 0.510.847343426 1 hCV11541681 rs2001490 hCV31840159 rs13013228 0.510.847343426 1 hCV11541681 rs2001490 hCV31840166 rs4513320 0.510.847343426 1 hCV11541681 rs2001490 hCV505733 rs11126416 0.510.847343426 0.8544 hCV11541681 rs2001490 hCV512569 rs6755500 0.510.847343426 0.9236 hCV11541681 rs2001490 hCV95670 rs4852975 0.510.847343426 1 hCV11541681 rs2001490 hCV95671 rs11126414 0.51 0.8473434261 hCV11541681 rs2001490 hCV95672 rs6750515 0.51 0.847343426 0.8515hCV11541681 rs2001490 hDV68778390 rs10188074 0.51 0.847343426 0.9596hCV11541681 rs2001490 hDV69785784 rs13000788 0.51 0.847343426 1hCV11541681 rs2001490 hDV70942181 rs17350056 0.51 0.847343426 1hCV11541681 rs2001490 hDV70953030 rs17434634 0.51 0.847343426 1hCV11541681 rs2001490 hDV70953035 rs17434655 0.51 0.847343426 1hCV11541681 rs2001490 hDV77051911 rs4852972 0.51 0.847343426 1hCV11541681 rs2001490 hDV77051912 rs4852976 0.51 0.847343426 0.9243hCV11786258 rs4253303 hCV11786147 rs4862662 0.51 0.09882857 0.6957hCV11786258 rs4253303 hCV11786203 rs4253251 0.51 0.09882857 0.1395hCV11786258 rs4253303 hCV11786235 rs4253287 0.51 0.09882857 0.116hCV11786258 rs4253303 hCV11786259 rs4253304 0.51 0.09882857 0.8944hCV11786258 rs4253303 hCV12066106 rs1914926 0.51 0.09882857 0.1036hCV11786258 rs4253303 hCV12066118 rs2048 0.51 0.09882857 0.5556hCV11786258 rs4253303 hCV12066119 rs1912826 0.51 0.09882857 0.4905hCV11786258 rs4253303 hCV12066124 rs2036914 0.51 0.09882857 0.3227hCV11786258 rs4253303 hCV15968025 rs2292425 0.51 0.09882857 0.3145hCV11786258 rs4253303 hCV15968026 rs2292426 0.51 0.09882857 0.2823hCV11786258 rs4253303 hCV15968034 rs2292428 0.51 0.09882857 0.337hCV11786258 rs4253303 hCV15968043 rs2292423 0.51 0.09882857 0.8913hCV11786258 rs4253303 hCV15975109 rs2304596 0.51 0.09882857 0.1395hCV11786258 rs4253303 hCV2103343 rs4241824 0.51 0.09882857 0.255hCV11786258 rs4253303 hCV2103348 rs11931515 0.51 0.09882857 0.116hCV11786258 rs4253303 hCV2103391 rs1008728 0.51 0.09882857 0.1419hCV11786258 rs4253303 hCV2103392 rs12500826 0.51 0.09882857 0.1267hCV11786258 rs4253303 hCV22271609 rs4253326 0.51 0.09882857 0.1138hCV11786258 rs4253303 hCV22272267 rs3733402 0.51 0.09882857 0.5632hCV11786258 rs4253303 hCV25474413 rs3822057 0.51 0.09882857 0.2622hCV11786258 rs4253303 hCV25474414 rs4253399 0.51 0.09882857 0.2697hCV11786258 rs4253303 hCV25634781 rs4253299 0.51 0.09882857 0.1325hCV11786258 rs4253303 hCV25989001 hCV25989001 0.51 0.09882857 0.1474hCV11786258 rs4253303 hCV25990131 rs13146272 0.51 0.09882857 0.3213hCV11786258 rs4253303 hCV26038139 rs4253405 0.51 0.09882857 0.1069hCV11786258 rs4253303 hCV26265197 rs10014399 0.51 0.09882857 0.1412hCV11786258 rs4253303 hCV26265199 rs2221843 0.51 0.09882857 0.1325hCV11786258 rs4253303 hCV26265231 rs7684025 0.51 0.09882857 0.5918hCV11786258 rs4253303 hCV27474895 rs3756011 0.51 0.09882857 0.1518hCV11786258 rs4253303 hCV27477533 rs3756008 0.51 0.09882857 0.315hCV11786258 rs4253303 hCV27482765 rs3775301 0.51 0.09882857 0.1395hCV11786258 rs4253303 hCV27506149 rs3822055 0.51 0.09882857 0.1325hCV11786258 rs4253303 hCV27902808 rs4253236 0.51 0.09882857 0.366hCV11786258 rs4253303 hCV28960679 rs6844764 0.51 0.09882857 0.3907hCV11786258 rs4253303 hCV29053260 rs4861707 0.51 0.09882857 0.1962hCV11786258 rs4253303 hCV29053264 rs7667777 0.51 0.09882857 0.7578hCV11786258 rs4253303 hCV29053265 rs4253244 0.51 0.09882857 0.3533hCV11786258 rs4253303 hCV29718000 rs4253238 0.51 0.09882857 0.5569hCV11786258 rs4253303 hCV29877725 rs4253295 0.51 0.09882857 1hCV11786258 rs4253303 hCV30983927 rs6552962 0.51 0.09882857 0.1072hCV11786258 rs4253303 hCV32209636 rs11132387 0.51 0.09882857 0.2106hCV11786258 rs4253303 hCV32209638 rs12507040 0.51 0.09882857 0.1024hCV11786258 rs4253303 hCV32291217 rs4253323 0.51 0.09882857 0.1395hCV11786258 rs4253303 hCV32291269 rs4253417 0.51 0.09882857 0.2035hCV11786258 rs4253303 hCV32291295 rs4253292 0.51 0.09882857 0.1404hCV11786258 rs4253303 hCV32291301 rs4253302 0.51 0.09882857 0.1385hCV11786258 rs4253303 hCV32295028 rs4253260 0.51 0.09882857 0.1395hCV11786258 rs4253303 hCV3229991 rs4241815 0.51 0.09882857 0.5632hCV11786258 rs4253303 hCV3229992 rs3775298 0.51 0.09882857 0.5632hCV11786258 rs4253303 hCV3229995 rs11132382 0.51 0.09882857 0.5569hCV11786258 rs4253303 hCV3230000 rs4253294 0.51 0.09882857 0.2479hCV11786258 rs4253303 hCV3230002 rs4253297 0.51 0.09882857 1 hCV11786258rs4253303 hCV3230003 rs2304595 0.51 0.09882857 0.8848 hCV11786258rs4253303 hCV3230006 rs4253308 0.51 0.09882857 1 hCV11786258 rs4253303hCV3230007 rs4253311 0.51 0.09882857 0.5632 hCV11786258 rs4253303hCV3230011 rs4253320 0.51 0.09882857 1 hCV11786258 rs4253303 hCV3230012rs4241821 0.51 0.09882857 0.1325 hCV11786258 rs4253303 hCV3230013rs3775303 0.51 0.09882857 0.8944 hCV11786258 rs4253303 hCV3230014rs4861709 0.51 0.09882857 0.2479 hCV11786258 rs4253303 hCV3230017rs4253327 0.51 0.09882857 0.2534 hCV11786258 rs4253303 hCV3230018rs925453 0.51 0.09882857 0.2319 hCV11786258 rs4253303 hCV3230019rs4253332 0.51 0.09882857 0.2319 hCV11786258 rs4253303 hCV3230022rs11132383 0.51 0.09882857 0.1658 hCV11786258 rs4253303 hCV3230025rs3756009 0.51 0.09882857 0.2464 hCV11786258 rs4253303 hCV3230038rs2289252 0.51 0.09882857 0.1956 hCV11786258 rs4253303 hCV3230083rs10013653 0.51 0.09882857 0.4797 hCV11786258 rs4253303 hCV3230084rs7682918 0.51 0.09882857 0.5961 hCV11786258 rs4253303 hCV3230094rs7687818 0.51 0.09882857 0.6447 hCV11786258 rs4253303 hCV3230096rs3817184 0.51 0.09882857 0.7346 hCV11786258 rs4253303 hCV3230097rs3736455 0.51 0.09882857 0.2761 hCV11786258 rs4253303 hCV3230101rs6835839 0.51 0.09882857 0.3578 hCV11786258 rs4253303 hCV3230106rs1473597 0.51 0.09882857 0.3534 hCV11786258 rs4253303 hCV3230110rs2276917 0.51 0.09882857 0.337 hCV11786258 rs4253303 hCV3230113rs1053094 0.51 0.09882857 0.491 hCV11786258 rs4253303 hCV3230125rs11938564 0.51 0.09882857 0.1367 hCV11786258 rs4253303 hCV3230131rs13136269 0.51 0.09882857 0.1024 hCV11786258 rs4253303 hCV3230133rs12511874 0.51 0.09882857 0.1024 hCV11786258 rs4253303 hCV3230134rs12500151 0.51 0.09882857 0.1024 hCV11786258 rs4253303 hCV3230136rs13116273 0.51 0.09882857 0.1243 hCV11786258 rs4253303 hCV32313006rs4253248 0.51 0.09882857 0.5569 hCV11786258 rs4253303 hCV32313024rs4253239 0.51 0.09882857 0.1404 hCV11786258 rs4253303 hCV32358975rs4253255 0.51 0.09882857 0.5556 hCV11786258 rs4253303 hCV32358984rs4253256 0.51 0.09882857 0.3667 hCV11786258 rs4253303 hCV8241630rs925451 0.51 0.09882857 0.2889 hCV11786258 rs4253303 hCV8241631rs1511802 0.51 0.09882857 1 hCV11786258 rs4253303 hCV8241632 rs15118010.51 0.09882857 0.5625 hCV11786258 rs4253303 hDV71222711 rs4253252 0.510.09882857 0.5569 hCV11786258 rs4253303 hDV76175111 rs35079309 0.510.09882857 0.1206 hCV11975250 rs6025 hCV11341861 rs10800436 0.510.015514847 0.1922 hCV11975250 rs6025 hCV11341869 rs2176473 0.510.015514847 0.0375 hCV11975250 rs6025 hCV11341876 rs1980198 0.510.015514847 0.0327 hCV11975250 rs6025 hCV11341878 rs4656670 0.510.015514847 0.0327 hCV11975250 rs6025 hCV11341882 rs12024897 0.510.015514847 0.0327 hCV11975250 rs6025 hCV11341898 rs12563090 0.510.015514847 0.0332 hCV11975250 rs6025 hCV11342138 rs2142760 0.510.015514847 0.0175 hCV11975250 rs6025 hCV11975194 rs2038024 0.510.015514847 0.0613 hCV11975250 rs6025 hCV11975195 rs1894692 0.510.015514847 1 hCV11975250 rs6025 hCV11975285 rs6127 0.51 0.0155148470.026 hCV11975250 rs6025 hCV11975296 rs6131 0.51 0.015514847 0.0848hCV11975250 rs6025 hCV11975318 rs1883228 0.51 0.015514847 0.0768hCV11975250 rs6025 hCV11975322 rs5357 0.51 0.015514847 0.0827hCV11975250 rs6025 hCV11975325 rs5367 0.51 0.015514847 0.1728hCV11975250 rs6025 hCV11975329 rs5363 0.51 0.015514847 0.1728hCV11975250 rs6025 hCV11975331 rs5362 0.51 0.015514847 0.1728hCV11975250 rs6025 hCV11975332 rs5361 0.51 0.015514847 0.1728hCV11975250 rs6025 hCV11975488 rs2057249 0.51 0.015514847 0.1728hCV11975250 rs6025 hCV15802103 rs2420370 0.51 0.015514847 0.117hCV11975250 rs6025 hCV15802110 rs2420371 0.51 0.015514847 0.3415hCV11975250 rs6025 hCV15858911 rs2806392 0.51 0.015514847 0.1655hCV11975250 rs6025 hCV15868017 rs2223303 0.51 0.015514847 0.0183hCV11975250 rs6025 hCV15878582 rs2275299 0.51 0.015514847 0.0327hCV11975250 rs6025 hCV15962928 rs2285211 0.51 0.015514847 0.0303hCV11975250 rs6025 hCV16161169 rs2205847 0.51 0.015514847 0.0872hCV11975250 rs6025 hCV16177404 rs2272920 0.51 0.015514847 0.1655hCV11975250 rs6025 hCV221700 rs6677410 0.51 0.015514847 0.0327hCV11975250 rs6025 hCV2217923 rs2014878 0.51 0.015514847 0.159hCV11975250 rs6025 hCV2456693 rs6672589 0.51 0.015514847 0.0169hCV11975250 rs6025 hCV2456695 rs10919173 0.51 0.015514847 0.0169hCV11975250 rs6025 hCV2456708 rs1517745 0.51 0.015514847 0.0544hCV11975250 rs6025 hCV2456730 rs961404 0.51 0.015514847 0.0327hCV11975250 rs6025 hCV2456733 rs12021580 0.51 0.015514847 0.0168hCV11975250 rs6025 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hCV29585595 rs10489173 0.510.015514847 0.1655 hCV11975250 rs6025 hCV29748285 rs6687813 0.510.015514847 0.3169 hCV11975250 rs6025 hCV29820280 rs6696217 0.510.015514847 0.2454 hCV11975250 rs6025 hCV30036721 rs3917449 0.510.015514847 0.0183 hCV11975250 rs6025 hCV30126935 rs6692451 0.510.015514847 0.1071 hCV11975250 rs6025 hCV30324835 rs10489183 0.510.015514847 0.0751 hCV11975250 rs6025 hCV30631277 rs10489182 0.510.015514847 0.0439 hCV11975250 rs6025 hCV32141371 rs10800447 0.510.015514847 0.0534 hCV11975250 rs6025 hCV32141374 rs10919174 0.510.015514847 0.0183 hCV11975250 rs6025 hCV32141406 rs10737547 0.510.015514847 0.1348 hCV11975250 rs6025 hCV32141457 rs6678795 0.510.015514847 0.0226 hCV11975250 rs6025 hCV32141484 rs3917768 0.510.015514847 0.0159 hCV11975250 rs6025 hCV32141485 rs3917744 0.510.015514847 0.0407 hCV11975250 rs6025 hCV32141499 rs3917862 0.510.015514847 0.1954 hCV11975250 rs6025 hCV32141505 rs3917657 0.510.015514847 0.1023 hCV11975250 rs6025 hCV32141519 rs12131631 0.510.015514847 0.1222 hCV11975250 rs6025 hCV32141520 rs12123695 0.510.015514847 0.0578 hCV11975250 rs6025 hCV32141521 rs10800462 0.510.015514847 0.0178 hCV11975250 rs6025 hCV32141522 rs12126695 0.510.015514847 0.0631 hCV11975250 rs6025 hCV32141523 rs10919204 0.510.015514847 0.0631 hCV11975250 rs6025 hCV32141527 rs10919207 0.510.015514847 0.0631 hCV11975250 rs6025 hCV32141586 rs12137905 0.510.015514847 0.0827 hCV11975250 rs6025 hCV32141621 rs12133642 0.510.015514847 0.1728 hCV11975250 rs6025 hCV32141622 rs12133666 0.510.015514847 0.1011 hCV11975250 rs6025 hCV32141631 rs3917436 0.510.015514847 0.0801 hCV11975250 rs6025 hCV32141639 rs3917411 0.510.015514847 0.1728 hCV11975250 rs6025 hCV32141645 rs3917452 0.510.015514847 0.1726 hCV11975250 rs6025 hCV32141663 rs12142587 0.510.015514847 0.0826 hCV11975250 rs6025 hCV32141665 rs10800470 0.510.015514847 0.0462 hCV11975250 rs6025 hCV32141669 rs10800472 0.510.015514847 0.0467 hCV11975250 rs6025 hCV32141741 rs12135361 0.510.015514847 0.1655 hCV11975250 rs6025 hCV32141779 rs12122767 0.510.015514847 0.14 hCV11975250 rs6025 hCV32141799 rs12133074 0.510.015514847 0.1655 hCV11975250 rs6025 hCV32141820 rs12132384 0.510.015514847 0.1655 hCV11975250 rs6025 hCV32141821 rs12135726 0.510.015514847 0.1655 hCV11975250 rs6025 hCV32141828 rs12136425 0.510.015514847 0.1655 hCV11975250 rs6025 hCV32141844 rs12142093 0.510.015514847 0.1655 hCV11975250 rs6025 hCV32141847 rs12143057 0.510.015514847 0.1655 hCV11975250 rs6025 hCV32141873 rs12131357 0.510.015514847 0.1803 hCV11975250 rs6025 hCV32141874 rs12121045 0.510.015514847 0.1655 hCV11975250 rs6025 hCV32141888 rs12124561 0.510.015514847 0.1655 hCV11975250 rs6025 hCV32141892 rs12125595 0.510.015514847 0.1655 hCV11975250 rs6025 hCV32141893 rs12125679 0.510.015514847 0.1655 hCV11975250 rs6025 hCV32141894 rs12128308 0.510.015514847 0.1587 hCV11975250 rs6025 hCV32141903 rs12131192 0.510.015514847 0.1655 hCV11975250 rs6025 hCV32141968 rs12124907 0.510.015514847 0.1728 hCV11975250 rs6025 hCV32141971 rs12118305 0.510.015514847 0.1018 hCV11975250 rs6025 hCV32398748 rs3917417 0.510.015514847 0.1167 hCV11975250 rs6025 hCV32398763 rs3917392 0.510.015514847 0.1728 hCV11975250 rs6025 hCV325211 rs3753305 0.510.015514847 0.0251 hCV11975250 rs6025 hCV325253 rs2236868 0.510.015514847 0.0246 hCV11975250 rs6025 hCV337817 rs9332586 0.510.015514847 0.0178 hCV11975250 rs6025 hCV474695 rs10800463 0.510.015514847 0.0244 hCV11975250 rs6025 hCV574681 rs575147 0.510.015514847 0.1072 hCV11975250 rs6025 hCV574682 rs590181 0.510.015514847 0.1655 hCV11975250 rs6025 hCV574683 rs544008 0.510.015514847 0.1655 hCV11975250 rs6025 hCV574693 rs601355 0.510.015514847 0.1655 hCV11975250 rs6025 hCV574707 rs565397 0.510.015514847 0.1655 hCV11975250 rs6025 hCV574726 rs664962 0.510.015514847 0.1655 hCV11975250 rs6025 hCV574743 rs545963 0.510.015514847 0.1724 hCV11975250 rs6025 hCV574757 rs654664 0.510.015514847 0.1728 hCV11975250 rs6025 hCV574764 rs638486 0.510.015514847 0.1728 hCV11975250 rs6025 hCV574785 rs511609 0.510.015514847 0.1583 hCV11975250 rs6025 hCV574788 rs629408 0.510.015514847 0.1726 hCV11975250 rs6025 hCV574789 rs629421 0.510.015514847 0.1726 hCV11975250 rs6025 hCV8688930 rs3905328 0.510.015514847 0.043 hCV11975250 rs6025 hCV8690976 rs1124843 0.510.015514847 0.0423 hCV11975250 rs6025 hCV8697031 rs1400836 0.510.015514847 0.0423 hCV11975250 rs6025 hCV8697043 rs1517747 0.510.015514847 0.0183 hCV11975250 rs6025 hCV8697049 rs1517744 0.510.015514847 0.0559 hCV11975250 rs6025 hCV8697055 rs1208134 0.510.015514847 0.1939 hCV11975250 rs6025 hCV8697995 rs4519 0.51 0.0155148470.1655 hCV11975250 rs6025 hCV8698056 rs488488 0.51 0.015514847 0.117hCV11975250 rs6025 hCV8698071 rs673789 0.51 0.015514847 0.1655hCV11975250 rs6025 hCV8919425 rs970740 0.51 0.015514847 0.1171hCV11975250 rs6025 hCV8919431 rs6009 0.51 0.015514847 0.2959 hCV11975250rs6025 hCV8919452 rs1018827 0.51 0.015514847 0.2769 hCV11975250 rs6025hCV8919485 rs1800808 0.51 0.015514847 0.0583 hCV11975250 rs6025hCV8919492 rs1569476 0.51 0.015514847 0.0303 hCV11975250 rs6025hCV8919494 rs1011267 0.51 0.015514847 0.0194 hCV11975250 rs6025hCV8919500 rs1011266 0.51 0.015514847 0.131 hCV11975250 rs6025hCV8919501 rs909628 0.51 0.015514847 0.1728 hCV11975250 rs6025hCV8919509 rs1051091 0.51 0.015514847 0.0872 hCV11975250 rs6025hCV8919515 rs1569457 0.51 0.015514847 0.0827 hCV11975250 rs6025hCV8919527 rs1800016 0.51 0.015514847 0.1655 hCV11975250 rs6025hCV8919528 rs1800015 0.51 0.015514847 0.1728 hCV11975250 rs6025hCV8919530 rs1805193 0.51 0.015514847 0.1728 hCV11975250 rs6025hCV9945935 rs3917750 0.51 0.015514847 0.0183 hCV11975250 rs6025hDV70670007 rs16828222 0.51 0.015514847 0.1655 hCV11975250 rs6025hDV70694593 rs16861990 0.51 0.015514847 0.1939 hCV11975250 rs6025hDV70695296 rs16862919 0.51 0.015514847 0.189 hCV11975250 rs6025hDV70695328 rs16862956 0.51 0.015514847 0.116 hCV11975250 rs6025hDV70695338 rs16862968 0.51 0.015514847 0.1728 hCV11975250 rs6025hDV70965007 rs17529304 0.51 0.015514847 0.1655 hCV11975250 rs6025hDV70966798 rs17543370 0.51 0.015514847 0.1651 hCV11975250 rs6025hDV70966830 rs17543611 0.51 0.015514847 0.1655 hCV11975250 rs6025hDV70974851 rs17601631 0.51 0.015514847 0.1655 hCV11975250 rs6025hDV70975002 rs17602701 0.51 0.015514847 0.1651 hCV11975250 rs6025hDV70975134 rs17603666 0.51 0.015514847 0.1655 hCV11975250 rs6025hDV71028805 rs4987299 0.51 0.015514847 0.1728 hCV11975250 rs6025hDV71028807 rs4987302 0.51 0.015514847 0.0827 hCV11975250 rs6025hDV71028808 rs4987304 0.51 0.015514847 0.0827 hCV11975250 rs6025hDV71028809 rs4987307 0.51 0.015514847 0.0827 hCV11975250 rs6025hDV71028811 rs4987318 0.51 0.015514847 0.033 hCV11975250 rs6025hDV71028814 rs4987323 0.51 0.015514847 0.1728 hCV11975250 rs6025hDV71028815 rs4987324 0.51 0.015514847 0.1728 hCV11975250 rs6025hDV71028816 rs4987325 0.51 0.015514847 0.0827 hCV11975250 rs6025hDV71028819 rs4987340 0.51 0.015514847 0.0827 hCV11975250 rs6025hDV71028821 rs4987343 0.51 0.015514847 0.0827 hCV11975250 rs6025hDV71028822 rs4987345 0.51 0.015514847 0.0826 hCV11975250 rs6025hDV71028828 rs4987395 0.51 0.015514847 0.0827 hCV11975250 rs6025hDV71070471 rs4987363 0.51 0.015514847 0.1728 hCV11975250 rs6025hDV76908547 rs3917400 0.51 0.015514847 0.103 hCV11975250 rs6025hDV76908557 rs3917427 0.51 0.015514847 0.1728 hCV11975250 rs6025hDV76908563 rs3917441 0.51 0.015514847 0.103 hCV11975250 rs6025hDV76908571 rs3917454 0.51 0.015514847 0.25 hCV11975250 rs6025hDV76908576 rs3917461 0.51 0.015514847 0.1592 hCV11975250 rs6025hDV76908651 rs3917729 0.51 0.015514847 0.0583 hCV11975250 rs6025hDV77030725 rs4656701 0.51 0.015514847 0.0804 hCV11975250 rs6025hDV77030727 rs4656703 0.51 0.015514847 0.0804 hCV12066124 rs2036914hCV11786147 rs4862662 0.51 0.050680687 0.2824 hCV12066124 rs2036914hCV11786203 rs4253251 0.51 0.050680687 0.0507 hCV12066124 rs2036914hCV11786235 rs4253287 0.51 0.050680687 0.0572 hCV12066124 rs2036914hCV11786258 rs4253303 0.51 0.050680687 0.3227 hCV12066124 rs2036914hCV11786259 rs4253304 0.51 0.050680687 0.3572 hCV12066124 rs2036914hCV11786295 rs4253421 0.51 0.050680687 0.1004 hCV12066124 rs2036914hCV11786307 rs1062547 0.51 0.050680687 0.4099 hCV12066124 rs2036914hCV11786327 rs13133050 0.51 0.050680687 0.1901 hCV12066124 rs2036914hCV12066116 rs1877320 0.51 0.050680687 0.1385 hCV12066124 rs2036914hCV12066118 rs2048 0.51 0.050680687 0.3579 hCV12066124 rs2036914hCV12066119 rs1912826 0.51 0.050680687 0.3713 hCV12066124 rs2036914hCV12066129 rs1593 0.51 0.050680687 0.1505 hCV12066124 rs2036914hCV12086148 rs1877321 0.51 0.050680687 0.0621 hCV12066124 rs2036914hCV15793897 rs3087505 0.51 0.050680687 0.1103 hCV12066124 rs2036914hCV15811716 rs2102575 0.51 0.050680687 0.1039 hCV12066124 rs2036914hCV15968025 rs2292425 0.51 0.050680687 0.175 hCV12066124 rs2036914hCV15968026 rs2292426 0.51 0.050680687 0.2128 hCV12066124 rs2036914hCV15968034 rs2292428 0.51 0.050680687 0.181 hCV12066124 rs2036914hCV15968043 rs2292423 0.51 0.050680687 0.3742 hCV12066124 rs2036914hCV15975109 rs2304596 0.51 0.050680687 0.0738 hCV12066124 rs2036914hCV16172925 rs2241818 0.51 0.050680687 0.0795 hCV12066124 rs2036914hCV16172935 rs2241817 0.51 0.050680687 0.4102 hCV12066124 rs2036914hCV2103337 rs13102931 0.51 0.050680687 0.0611 hCV12066124 rs2036914hCV2103343 rs4241824 0.51 0.050680687 0.9265 hCV12066124 rs2036914hCV2103375 rs12502630 0.51 0.050680687 0.0643 hCV12066124 rs2036914hCV2103388 rs4613610 0.51 0.050680687 0.0917 hCV12066124 rs2036914hCV2103391 rs1008728 0.51 0.050680687 0.2419 hCV12066124 rs2036914hCV2103392 rs12500826 0.51 0.050680687 0.3937 hCV12066124 rs2036914hCV2103401 rs7687352 0.51 0.050680687 0.0531 hCV12066124 rs2036914hCV2103402 rs9993749 0.51 0.050680687 0.0695 hCV12066124 rs2036914hCV22272267 rs3733402 0.51 0.050680687 0.3605 hCV12066124 rs2036914hCV25474413 rs3822057 0.51 0.050680687 0.9449 hCV12066124 rs2036914hCV25474414 rs4253399 0.51 0.050680687 0.5632 hCV12066124 rs2036914hCV25634763 rs4253241 0.51 0.050680687 0.0841 hCV12066124 rs2036914hCV25988221 rs9995366 0.51 0.050680687 0.0931 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rs12436642 0.51 0.445188644 0.9381 hCV16182835 rs2274736hCV32095430 rs11159859 0.51 0.445188644 0.8539 hCV16182835 rs2274736hCV32095431 rs11629164 0.51 0.445188644 0.8395 hCV16182835 rs2274736hCV32095460 rs12434935 0.51 0.445188644 0.6651 hCV16182835 rs2274736hCV32095525 rs12590826 0.51 0.445188644 0.6121 hCV16182835 rs2274736hCV32095533 rs12588535 0.51 0.445188644 0.6651 hCV16182835 rs2274736hCV3211521 rs12431548 0.51 0.445188644 0.6512 hCV16182835 rs2274736hCV3211539 rs1998670 0.51 0.445188644 0.6891 hCV16182835 rs2274736hCV3211540 rs2274735 0.51 0.445188644 0.9793 hCV16182835 rs2274736hCV3211544 rs9323830 0.51 0.445188644 0.919 hCV16182835 rs2274736hCV3211545 rs7160647 0.51 0.445188644 0.9163 hCV16182835 rs2274736hCV3211546 rs7143642 0.51 0.445188644 0.919 hCV16182835 rs2274736hCV3211548 rs7151164 0.51 0.445188644 0.919 hCV16182835 rs2274736hCV3211549 rs12433026 0.51 0.445188644 0.8973 hCV16182835 rs2274736hCV3211559 rs2004329 0.51 0.445188644 0.6919 hCV16182835 rs2274736hCV3211560 rs12436326 0.51 0.445188644 0.6988 hCV16182835 rs2274736hCV3211561 rs8017811 0.51 0.445188644 0.9581 hCV16182835 rs2274736hCV3211562 rs4904454 0.51 0.445188644 0.9596 hCV16182835 rs2274736hCV3211566 rs930181 0.51 0.445188644 0.9591 hCV16182835 rs2274736hCV3211568 rs816075 0.51 0.445188644 1 hCV16182835 rs2274736 hCV342703rs12433464 0.51 0.445188644 0.6601 hCV16182835 rs2274736 hCV342704rs1955598 0.51 0.445188644 0.7953 hCV16182835 rs2274736 hCV7583060rs1028455 0.51 0.445188644 0.8774 hCV16182835 rs2274736 hCV7583094rs1048190 0.51 0.445188644 0.6083 hCV16182835 rs2274736 hCV9595812rs845758 0.51 0.445188644 0.822 hCV16182835 rs2274736 hCV9595827rs845757 0.51 0.445188644 0.9591 hCV16182835 rs2274736 hCV9595840rs816072 0.51 0.445188644 1 hCV16182835 rs2274736 hCV9595849 rs11523760.51 0.445188644 0.9793 hCV16182835 rs2274736 hCV9595856 rs816069 0.510.445188644 0.9586 hCV16182835 rs2274736 hCV9595863 rs1344747 0.510.445188644 0.9596 hCV16182835 rs2274736 hCV9595868 rs891750 0.510.445188644 0.6812 hCV16182835 rs2274736 hCV9595869 rs891749 0.510.445188644 0.6812 hCV16182835 rs2274736 hCV9595897 rs1287825 0.510.445188644 0.4565 hCV16182835 rs2274736 hDV70886228 rs17124652 0.510.445188644 0.6583 hCV16182835 rs2274736 hDV70886264 rs17124700 0.510.445188644 0.6583 hCV16182835 rs2274736 hDV70918505 rs17188228 0.510.445188644 0.6141 hCV16182835 rs2274736 hDV70929207 rs17260380 0.510.445188644 0.6481 hCV16182835 rs2274736 hDV70929214 rs17260415 0.510.445188644 0.6571 hCV16182835 rs2274736 hDV70991668 rs17698817 0.510.445188644 0.6223 hCV16182835 rs2274736 hDV70991980 rs17700521 0.510.445188644 0.5853 hCV16182835 rs2274736 hDV71004484 rs17772064 0.510.445188644 0.6697 hCV16182835 rs2274736 hDV71004511 rs17772222 0.510.445188644 0.6697 hCV16182835 rs2274736 hDV71004521 rs17772288 0.510.445188644 0.65 hCV16182835 rs2274736 hDV71008979 rs17798341 0.510.445188644 0.6988 hCV16182835 rs2274736 hDV71605687 rs17188046 0.510.445188644 0.6571 hCV16182835 rs2274736 hDV77012938 rs4514599 0.510.445188644 0.8712 hCV16182835 rs2274736 hDV77027209 rs4635267 0.510.445188644 0.6646 hCV16182835 rs2274736 hDV77248933 rs8021690 0.510.445188644 0.6481 hCV1825046 rs2069952 hCV1064756 rs734111 0.510.131481735 0.5093 hCV1825046 rs2069952 hCV11189130 rs2065979 0.510.131481735 1 hCV1825046 rs2069952 hCV11189159 rs6060270 0.510.131481735 0.2033 hCV1825046 rs2069952 hCV11189164 rs3746427 0.510.131481735 1 hCV1825046 rs2069952 hCV11189240 rs2038504 0.510.131481735 0.7662 hCV1825046 rs2069952 hCV11189318 rs7263251 0.510.131481735 0.1718 hCV1825046 rs2069952 hCV11189331 rs6087649 0.510.131481735 0.5093 hCV1825046 rs2069952 hCV11189332 rs2273683 0.510.131481735 0.4987 hCV1825046 rs2069952 hCV11189369 rs6119535 0.510.131481735 0.2714 hCV1825046 rs2069952 hCV11189450 rs6060048 0.510.131481735 0.3343 hCV1825046 rs2069952 hCV11656916 rs7004 0.510.131481735 0.1338 hCV1825046 rs2069952 hCV11656971 rs2050652 0.510.131481735 0.3132 hCV1825046 rs2069952 hCV11656979 rs2065108 0.510.131481735 0.4684 hCV1825046 rs2069952 hCV11656982 rs1885115 0.510.131481735 0.3304 hCV1825046 rs2069952 hCV11656983 rs1998233 0.510.131481735 0.2712 hCV1825046 rs2069952 hCV11656986 rs1885119 0.510.131481735 0.4132 hCV1825046 rs2069952 hCV1207858 rs6141514 0.510.131481735 0.2888 hCV1825046 rs2069952 hCV1207862 rs6119524 0.510.131481735 0.2714 hCV1825046 rs2069952 hCV1207879 rs2295354 0.510.131481735 0.2537 hCV1825046 rs2069952 hCV1207880 rs2295353 0.510.131481735 0.2714 hCV1825046 rs2069952 hCV1207887 rs959829 0.510.131481735 0.5093 hCV1825046 rs2069952 hCV1207889 rs1998028 0.510.131481735 0.3128 hCV1825046 rs2069952 hCV1207890 rs6087625 0.510.131481735 0.2714 hCV1825046 rs2069952 hCV1207891 rs2378259 0.510.131481735 0.3343 hCV1825046 rs2069952 hCV1207893 rs6087624 0.510.131481735 0.3703 hCV1825046 rs2069952 hCV1207895 rs6120708 0.510.131481735 0.2714 hCV1825046 rs2069952 hCV1207897 rs3787222 0.510.131481735 0.3012 hCV1825046 rs2069952 hCV1207898 rs1018503 0.510.131481735 0.3343 hCV1825046 rs2069952 hCV1207902 rs2295352 0.510.131481735 0.5351 hCV1825046 rs2069952 hCV1207903 rs6087623 0.510.131481735 0.3128 hCV1825046 rs2069952 hCV1207909 rs6119512 0.510.131481735 0.3128 hCV1825046 rs2069952 hCV1207914 rs910870 0.510.131481735 0.3128 hCV1825046 rs2069952 hCV1207915 rs910869 0.510.131481735 0.2471 hCV1825046 rs2069952 hCV1265078 rs6088569 0.510.131481735 0.4047 hCV1825046 rs2069952 hCV1265079 rs6088570 0.510.131481735 0.4069 hCV1825046 rs2069952 hCV1265082 rs6088575 0.510.131481735 0.4069 hCV1825046 rs2069952 hCV1265086 rs2378251 0.510.131481735 0.4069 hCV1825046 rs2069952 hCV1265087 rs2889855 0.510.131481735 0.4069 hCV1825046 rs2069952 hCV1265092 rs6088578 0.510.131481735 0.4403 hCV1825046 rs2069952 hCV1265109 rs6058108 0.510.131481735 0.2714 hCV1825046 rs2069952 hCV1271625 rs6060341 0.510.131481735 0.1454 hCV1825046 rs2069952 hCV1271649 rs6120880 0.510.131481735 0.3283 hCV1825046 rs2069952 hCV1271653 rs2425019 0.510.131481735 0.1786 hCV1825046 rs2069952 hCV1271661 rs6088765 0.510.131481735 0.2649 hCV1825046 rs2069952 hCV1271671 rs2093058 0.510.131481735 1 hCV1825046 rs2069952 hCV1271676 rs1577924 0.51 0.1314817351 hCV1825046 rs2069952 hCV1271685 rs663550 0.51 0.131481735 0.9658hCV1825046 rs2069952 hCV1271688 rs6058202 0.51 0.131481735 1 hCV1825046rs2069952 hCV1347919 rs1058003 0.51 0.131481735 0.4132 hCV1825046rs2069952 hCV1347925 rs6120790 0.51 0.131481735 0.1339 hCV1825046rs2069952 hCV1347930 rs3736802 0.51 0.131481735 0.4897 hCV1825046rs2069952 hCV1347943 rs6060164 0.51 0.131481735 0.3948 hCV1825046rs2069952 hCV1347944 rs6087660 0.51 0.131481735 0.4132 hCV1825046rs2069952 hCV1347963 rs13042358 0.51 0.131481735 0.7561 hCV1825046rs2069952 hCV1348023 rs6087677 0.51 0.131481735 0.4741 hCV1825046rs2069952 hCV1361222 rs3818273 0.51 0.131481735 0.5093 hCV1825046rs2069952 hCV1361223 rs3746450 0.51 0.131481735 0.5351 hCV1825046rs2069952 hCV15860322 rs2069948 0.51 0.131481735 1 hCV1825046 rs2069952hCV15870054 rs2224320 0.51 0.131481735 0.429 hCV1825046 rs2069952hCV15876219 rs2281626 0.51 0.131481735 0.2747 hCV1825046 rs2069952hCV16003843 rs2378332 0.51 0.131481735 0.3948 hCV1825046 rs2069952hCV16013546 rs2425012 0.51 0.131481735 0.7218 hCV1825046 rs2069952hCV16013558 rs2425009 0.51 0.131481735 0.2569 hCV1825046 rs2069952hCV16013570 rs2077574 0.51 0.131481735 0.2569 hCV1825046 rs2069952hCV16013581 rs2253484 0.51 0.131481735 0.4987 hCV1825046 rs2069952hCV16013593 rs2425001 0.51 0.131481735 0.3727 hCV1825046 rs2069952hCV16013594 rs2424999 0.51 0.131481735 0.5093 hCV1825046 rs2069952hCV16013698 rs2425052 0.51 0.131481735 0.1551 hCV1825046 rs2069952hCV16013724 rs2425044 0.51 0.131481735 0.158 hCV1825046 rs2069952hCV16076405 rs2145557 0.51 0.131481735 0.4321 hCV1825046 rs2069952hCV16179579 rs2273684 0.51 0.131481735 0.3893 hCV1825046 rs2069952hCV16179908 rs2273805 0.51 0.131481735 0.4805 hCV1825046 rs2069952hCV16190708 rs2295701 0.51 0.131481735 0.2554 hCV1825046 rs2069952hCV16191203 rs2295887 0.51 0.131481735 0.4684 hCV1825046 rs2069952hCV16191204 rs2295886 0.51 0.131481735 0.3062 hCV1825046 rs2069952hCV16191205 rs2295885 0.51 0.131481735 0.3062 hCV1825046 rs2069952hCV1825004 rs1415771 0.51 0.131481735 0.7302 hCV1825046 rs2069952hCV1825005 rs945959 0.51 0.131481735 0.7327 hCV1825046 rs2069952hCV1825006 rs1124511 0.51 0.131481735 0.7327 hCV1825046 rs2069952hCV1825018 rs11696967 0.51 0.131481735 0.2033 hCV1825046 rs2069952hCV1825019 rs6088732 0.51 0.131481735 0.2033 hCV1825046 rs2069952hCV1825021 rs6088733 0.51 0.131481735 0.2195 hCV1825046 rs2069952hCV1825025 rs6088738 0.51 0.131481735 0.2033 hCV1825046 rs2069952hCV1825040 rs6060278 0.51 0.131481735 0.2033 hCV1825046 rs2069952hCV1825047 rs9574 0.51 0.131481735 1 hCV1825046 rs2069952 hCV1825056rs6060285 0.51 0.131481735 0.9635 hCV1825046 rs2069952 hCV1825062rs6087685 0.51 0.131481735 0.2311 hCV1825046 rs2069952 hCV2142560rs4911449 0.51 0.131481735 0.5093 hCV1825046 rs2069952 hCV2142561rs4911450 0.51 0.131481735 0.5351 hCV1825046 rs2069952 hCV2142562rs4911451 0.51 0.131481735 0.5486 hCV1825046 rs2069952 hCV2142566rs6088650 0.51 0.131481735 0.5093 hCV1825046 rs2069952 hCV2142567rs725521 0.51 0.131481735 0.5093 hCV1825046 rs2069952 hCV2142575rs2236270 0.51 0.131481735 0.2714 hCV1825046 rs2069952 hCV2142576rs2236271 0.51 0.131481735 0.5093 hCV1825046 rs2069952 hCV2142578rs6088655 0.51 0.131481735 0.5093 hCV1825046 rs2069952 hCV2142584rs3761144 0.51 0.131481735 0.6325 hCV1825046 rs2069952 hCV2142586rs6060130 0.51 0.131481735 0.6325 hCV1825046 rs2069952 hCV2142587rs6088664 0.51 0.131481735 0.6283 hCV1825046 rs2069952 hCV2142597rs6120778 0.51 0.131481735 0.7561 hCV1825046 rs2069952 hCV2142599rs6060140 0.51 0.131481735 0.7561 hCV1825046 rs2069952 hCV2142611rs1885114 0.51 0.131481735 0.7561 hCV1825046 rs2069952 hCV2142616rs3746438 0.51 0.131481735 0.6906 hCV1825046 rs2069952 hCV2521759rs2076668 0.51 0.131481735 0.3128 hCV1825046 rs2069952 hCV2521760rs6088624 0.51 0.131481735 0.3189 hCV1825046 rs2069952 hCV2521763rs12625149 0.51 0.131481735 0.255 hCV1825046 rs2069952 hCV2521764rs12626122 0.51 0.131481735 0.2714 hCV1825046 rs2069952 hCV2521776rs6087634 0.51 0.131481735 0.5093 hCV1825046 rs2069952 hCV25619953rs6060151 0.51 0.131481735 0.4132 hCV1825046 rs2069952 hCV25619954rs4911462 0.51 0.131481735 0.4132 hCV1825046 rs2069952 hCV25619982rs6120838 0.51 0.131481735 0.5278 hCV1825046 rs2069952 hCV25750225rs4911163 0.51 0.131481735 0.5093 hCV1825046 rs2069952 hCV27166951rs6087663 0.51 0.131481735 0.2569 hCV1825046 rs2069952 hCV27166987rs6119542 0.51 0.131481735 0.5351 hCV1825046 rs2069952 hCV27166995rs6088618 0.51 0.131481735 0.4255 hCV1825046 rs2069952 hCV27166997rs6088615 0.51 0.131481735 0.2714 hCV1825046 rs2069952 hCV27167007rs2180276 0.51 0.131481735 0.3128 hCV1825046 rs2069952 hCV27167022rs6060013 0.51 0.131481735 0.3242 hCV1825046 rs2069952 hCV27167045rs2378252 0.51 0.131481735 0.2702 hCV1825046 rs2069952 hCV27167691rs2378333 0.51 0.131481735 0.4684 hCV1825046 rs2069952 hCV27167696rs6088716 0.51 0.131481735 0.4698 hCV1825046 rs2069952 hCV27472681rs3746430 0.51 0.131481735 0.2569 hCV1825046 rs2069952 hCV27486123rs3803937 0.51 0.131481735 0.4167 hCV1825046 rs2069952 hCV27503616rs3803938 0.51 0.131481735 0.4132 hCV1825046 rs2069952 hCV27833500rs17092385 0.51 0.131481735 0.15 hCV1825046 rs2069952 hCV27893015rs4911167 0.51 0.131481735 0.4132 hCV1825046 rs2069952 hCV27893018rs4911441 0.51 0.131481735 0.3592 hCV1825046 rs2069952 hCV27982387rs4911460 0.51 0.131481735 0.3948 hCV1825046 rs2069952 hCV28004288rs4911455 0.51 0.131481735 0.1718 hCV1825046 rs2069952 hCV29372788rs6060163 0.51 0.131481735 0.2554 hCV1825046 rs2069952 hCV29372800rs6058149 0.51 0.131481735 0.1519 hCV1825046 rs2069952 hCV29372802rs6579204 0.51 0.131481735 0.2141 hCV1825046 rs2069952 hCV29372803rs6088659 0.51 0.131481735 0.1833 hCV1825046 rs2069952 hCV29372811rs7266550 0.51 0.131481735 0.5093 hCV1825046 rs2069952 hCV29372820rs6120739 0.51 0.131481735 0.5093 hCV1825046 rs2069952 hCV29372834rs6060001 0.51 0.131481735 0.3893 hCV1825046 rs2069952 hCV29373050rs6088722 0.51 0.131481735 0.3062 hCV1825046 rs2069952 hCV29373051rs6142300 0.51 0.131481735 0.3062 hCV1825046 rs2069952 hCV29373055rs6060196 0.51 0.131481735 0.2707 hCV1825046 rs2069952 hCV29530377rs6088747 0.51 0.131481735 1 hCV1825046 rs2069952 hCV29530378 rs60581790.51 0.131481735 0.3062 hCV1825046 rs2069952 hCV29566578 rs6060172 0.510.131481735 0.3948 hCV1825046 rs2069952 hCV29584663 rs6060162 0.510.131481735 0.3948 hCV1825046 rs2069952 hCV29620866 rs6088724 0.510.131481735 0.4805 hCV1825046 rs2069952 hCV29638959 rs6060154 0.510.131481735 0.2554 hCV1825046 rs2069952 hCV29674936 rs6087618 0.510.131481735 0.307 hCV1825046 rs2069952 hCV29674974 rs6058224 0.510.131481735 0.158 hCV1825046 rs2069952 hCV29674976 rs6060266 0.510.131481735 0.1983 hCV1825046 rs2069952 hCV2969302 rs6120730 0.510.131481735 0.3454 hCV1825046 rs2069952 hCV2969304 rs2424997 0.510.131481735 0.3343 hCV1825046 rs2069952 hCV2969305 rs6060052 0.510.131481735 0.323 hCV1825046 rs2069952 hCV29693115 rs6119534 0.510.131481735 0.2714 hCV1825046 rs2069952 hCV29693120 rs6060003 0.510.131481735 0.3893 hCV1825046 rs2069952 hCV29693169 rs6058192 0.510.131481735 0.2935 hCV1825046 rs2069952 hCV29711231 rs6119536 0.510.131481735 0.5351 hCV1825046 rs2069952 hCV29729418 rs6142294 0.510.131481735 0.8242 hCV1825046 rs2069952 hCV29747405 rs6088640 0.510.131481735 0.5093 hCV1825046 rs2069952 hCV29747445 rs6060199 0.510.131481735 0.7956 hCV1825046 rs2069952 hCV29783257 rs6087619 0.510.131481735 0.2714 hCV1825046 rs2069952 hCV29819450 rs4142034 0.510.131481735 0.2554 hCV1825046 rs2069952 hCV29837701 rs6060045 0.510.131481735 0.3343 hCV1825046 rs2069952 hCV29837747 rs6088728 0.510.131481735 0.4684 hCV1825046 rs2069952 hCV29837748 rs6088721 0.510.131481735 0.4684 hCV1825046 rs2069952 hCV29855628 rs6058150 0.510.131481735 0.1718 hCV1825046 rs2069952 hCV29855681 rs6087683 0.510.131481735 1 hCV1825046 rs2069952 hCV29855684 rs6120816 0.510.131481735 0.4132 hCV1825046 rs2069952 hCV2988252 rs2425005 0.510.131481735 0.5351 hCV1825046 rs2069952 hCV2988253 rs6087632 0.510.131481735 0.2714 hCV1825046 rs2069952 hCV2988254 rs6060064 0.510.131481735 0.5093 hCV1825046 rs2069952 hCV29909897 rs6142324 0.510.131481735 1 hCV1825046 rs2069952 hCV29909901 rs6060205 0.510.131481735 0.4332 hCV1825046 rs2069952 hCV29945782 rs6087626 0.510.131481735 0.2714 hCV1825046 rs2069952 hCV29963933 rs6088590 0.510.131481735 0.2714 hCV1825046 rs2069952 hCV29982069 rs6060170 0.510.131481735 0.3857 hCV1825046 rs2069952 hCV29982073 rs6088580 0.510.131481735 0.4112 hCV1825046 rs2069952 hCV30000150 rs4911465 0.510.131481735 0.2707 hCV1825046 rs2069952 hCV30035910 rs6088692 0.510.131481735 0.4132 hCV1825046 rs2069952 hCV30053848 rs6088687 0.510.131481735 0.3948 hCV1825046 rs2069952 hCV30053849 rs6088677 0.510.131481735 0.2554 hCV1825046 rs2069952 hCV30053852 rs6088660 0.510.131481735 0.1575 hCV1825046 rs2069952 hCV30072029 rs6119516 0.510.131481735 0.2714 hCV1825046 rs2069952 hCV30090036 rs6120747 0.510.131481735 0.2714 hCV1825046 rs2069952 hCV3010271 rs2889861 0.510.131481735 0.5093 hCV1825046 rs2069952 hCV30126097 rs6120827 0.510.131481735 0.2707 hCV1825046 rs2069952 hCV30144027 rs6119559 0.510.131481735 0.2569 hCV1825046 rs2069952 hCV30162176 rs6060127 0.510.131481735 0.1698 hCV1825046 rs2069952 hCV30162181 rs6120723 0.510.131481735 0.2714 hCV1825046 rs2069952 hCV30180146 rs6060216 0.510.131481735 0.4122 hCV1825046 rs2069952 hCV30198062 rs6088764 0.510.131481735 0.2291 hCV1825046 rs2069952 hCV30270039 rs6060301 0.510.131481735 0.4086 hCV1825046 rs2069952 hCV30323913 rs6060137 0.510.131481735 0.2554 hCV1825046 rs2069952 hCV30323914 rs6087657 0.510.131481735 0.2569 hCV1825046 rs2069952 hCV30342005 rs6060133 0.510.131481735 0.198 hCV1825046 rs2069952 hCV30342055 rs6088727 0.510.131481735 0.4684 hCV1825046 rs2069952 hCV30360331 rs6088568 0.510.131481735 0.4069 hCV1825046 rs2069952 hCV30360384 rs6058194 0.510.131481735 0.2195 hCV1825046 rs2069952 hCV30378399 rs6141509 0.510.131481735 0.3343 hCV1825046 rs2069952 hCV30378437 rs6088713 0.510.131481735 0.3062 hCV1825046 rs2069952 hCV30396340 rs6120849 0.510.131481735 0.216 hCV1825046 rs2069952 hCV30450320 rs4911478 0.510.131481735 1 hCV1825046 rs2069952 hCV30450323 rs6058166 0.510.131481735 0.4122 hCV1825046 rs2069952 hCV30468101 rs6088735 0.510.131481735 0.2033 hCV1825046 rs2069952 hCV30485907 rs6087653 0.510.131481735 0.5093 hCV1825046 rs2069952 hCV30503905 rs4911165 0.510.131481735 0.1823 hCV1825046 rs2069952 hCV30503911 rs4911161 0.510.131481735 0.5093 hCV1825046 rs2069952 hCV30503955 rs6060194 0.510.131481735 0.2554 hCV1825046 rs2069952 hCV30540259 rs6087664 0.510.131481735 0.4132 hCV1825046 rs2069952 hCV30558455 rs6088638 0.510.131481735 0.1462 hCV1825046 rs2069952 hCV30594383 rs6060038 0.510.131481735 0.3343 hCV1825046 rs2069952 hCV30612241 rs6060168 0.510.131481735 0.7561 hCV1825046 rs2069952 hCV30612290 rs6060250 0.510.131481735 0.3355 hCV1825046 rs2069952 hCV30630342 rs6141526 0.510.131481735 0.7713 hCV1825046 rs2069952 hCV30630345 rs4911456 0.510.131481735 0.2554 hCV1825046 rs2069952 hCV32066111 rs10875492 0.510.131481735 0.3927 hCV1825046 rs2069952 hCV32066659 rs7272884 0.510.131481735 0.158 hCV1825046 rs2069952 hCV3249260 rs7263157 0.510.131481735 0.5093 hCV1825046 rs2069952 hCV3249262 rs6120750 0.510.131481735 0.2537 hCV1825046 rs2069952 hCV3249263 rs6088635 0.510.131481735 0.5093 hCV1825046 rs2069952 hCV3249264 rs6087641 0.510.131481735 0.5093 hCV1825046 rs2069952 hCV3249268 rs6058137 0.510.131481735 0.5093 hCV1825046 rs2069952 hCV3249269 rs8116657 0.510.131481735 0.5351 hCV1825046 rs2069952 hCV3249271 rs4911164 0.510.131481735 0.5351 hCV1825046 rs2069952 hCV3249272 rs6087644 0.510.131481735 0.5123 hCV1825046 rs2069952 hCV3249275 rs6088642 0.510.131481735 0.5093 hCV1825046 rs2069952 hCV3249278 rs6120757 0.510.131481735 0.5093 hCV1825046 rs2069952 hCV3249279 rs926734 0.510.131481735 0.5093 hCV1825046 rs2069952 hCV3249280 rs6120758 0.510.131481735 0.5093 hCV1825046 rs2069952 hCV3249282 rs2064454 0.510.131481735 0.5093 hCV1825046 rs2069952 hCV3249286 rs6088646 0.510.131481735 0.5093 hCV1825046 rs2069952 hCV3249289 rs2223881 0.510.131481735 0.5351 hCV1825046 rs2069952 hCV3249290 rs2076667 0.510.131481735 0.5093 hCV1825046 rs2069952 hCV3249293 rs6058154 0.510.131481735 0.7561 hCV1825046 rs2069952 hCV599565 rs633198 0.510.131481735 1 hCV1825046 rs2069952 hCV624502 rs666210 0.51 0.1314817350.2804 hCV1825046 rs2069952 hCV624503 rs633784 0.51 0.131481735 0.2804hCV1825046 rs2069952 hCV7499886 rs1415774 0.51 0.131481735 1 hCV1825046rs2069952 hCV7593276 rs1535466 0.51 0.131481735 0.3224 hCV1825046rs2069952 hCV7593320 rs1060615 0.51 0.131481735 0.4769 hCV1825046rs2069952 hCV7593321 rs1013677 0.51 0.131481735 0.5093 hCV1825046rs2069952 hCV7593328 rs1018447 0.51 0.131481735 0.5093 hCV1825046rs2069952 hDV70862585 rs17092209 0.51 0.131481735 0.1405 hCV1825046rs2069952 hDV70862720 rs17092378 0.51 0.131481735 0.3132 hCV1825046rs2069952 hDV70936356 rs17310782 0.51 0.131481735 0.2554 hCV1825046rs2069952 hDV71833331 rs6142280 0.51 0.131481735 0.7559 hCV1825046rs2069952 hDV71898298 rs7361656 0.51 0.131481735 0.2982 hCV1825046rs2069952 hDV72053898 rs8114671 0.51 0.131481735 1 hCV1841975 rs1799810hCV11263777 rs11683986 0.51 0.254914511 0.4647 hCV1841975 rs1799810hCV11263786 rs13408910 0.51 0.254914511 0.429 hCV1841975 rs1799810hCV11266746 rs6753288 0.51 0.254914511 0.834 hCV1841975 rs1799810hCV11266765 rs11679414 0.51 0.254914511 0.5751 hCV1841975 rs1799810hCV11268771 rs4662718 0.51 0.254914511 0.5598 hCV1841975 rs1799810hCV12046224 rs10850 0.51 0.254914511 0.5598 hCV1841975 rs1799810hCV1441133 rs7568070 0.51 0.254914511 0.356 hCV1841975 rs1799810hCV1441173 rs4536600 0.51 0.254914511 0.641 hCV1841975 rs1799810hCV1441189 rs4150499 0.51 0.254914511 0.5379 hCV1841975 rs1799810hCV1441196 rs4150474 0.51 0.254914511 0.5354 hCV1841975 rs1799810hCV15860236 rs2069904 0.51 0.254914511 0.7263 hCV1841975 rs1799810hCV169044 rs11691088 0.51 0.254914511 0.5832 hCV1841975 rs1799810hCV1841983 rs5937 0.51 0.254914511 0.6119 hCV1841975 rs1799810hCV25630050 rs3732209 0.51 0.254914511 0.5787 hCV1841975 rs1799810hCV25960135 rs4150402 0.51 0.254914511 0.5598 hCV1841975 rs1799810hCV26980926 rs4150471 0.51 0.254914511 0.5379 hCV1841975 rs1799810hCV273435 rs7607907 0.51 0.254914511 0.5598 hCV1841975 rs1799810hCV27907596 rs4321325 0.51 0.254914511 0.335 hCV1841975 rs1799810hCV27964958 rs4662713 0.51 0.254914511 0.5598 hCV1841975 rs1799810hCV28026949 rs4662720 0.51 0.254914511 0.5598 hCV1841975 rs1799810hCV28952331 rs6755028 0.51 0.254914511 0.5319 hCV1841975 rs1799810hCV28955091 rs7567389 0.51 0.254914511 0.3991 hCV1841975 rs1799810hCV28955092 rs6430936 0.51 0.254914511 0.5598 hCV1841975 rs1799810hCV28966787 rs7585314 0.51 0.254914511 0.5343 hCV1841975 rs1799810hCV29570359 rs6738690 0.51 0.254914511 0.5288 hCV1841975 rs1799810hCV29636350 rs10496661 0.51 0.254914511 0.5598 hCV1841975 rs1799810hCV30166207 rs7590030 0.51 0.254914511 0.5787 hCV1841975 rs1799810hCV30418053 rs6757492 0.51 0.254914511 0.545 hCV1841975 rs1799810hCV30598525 rs7556675 0.51 0.254914511 0.5598 hCV1841975 rs1799810hCV30711743 rs11890243 0.51 0.254914511 0.4437 hCV1841975 rs1799810hCV31814195 rs11680949 0.51 0.254914511 0.5659 hCV1841975 rs1799810hCV31814218 rs6430938 0.51 0.254914511 0.6123 hCV1841975 rs1799810hCV8806682 rs1011019 0.51 0.254914511 0.5598 hCV1841975 rs1799810hCV8807983 rs1504136 0.51 0.254914511 0.5343 hCV1841975 rs1799810hCV8807988 rs3893313 0.51 0.254914511 0.2563 hCV1841975 rs1799810hCV8807993 rs1473623 0.51 0.254914511 0.5478 hCV1841975 rs1799810hCV8810479 rs1604817 0.51 0.254914511 0.6417 hCV1841975 rs1799810hCV8810750 rs1158867 0.51 0.254914511 1 hCV1841975 rs1799810 hCV9465822rs11683427 0.51 0.254914511 0.3486 hCV1841975 rs1799810 hCV9468542rs7599210 0.51 0.254914511 0.8322 hCV1841975 rs1799810 hDV75209985rs2069898 0.51 0.254914511 0.7164 hCV1841983 rs5937 hCV1023645 rs3341600.51 0.289879478 0.3788 hCV1841983 rs5937 hCV1023646 rs334159 0.510.289879478 0.3408 hCV1841983 rs5937 hCV1023653 rs334151 0.510.289879478 0.3788 hCV1841983 rs5937 hCV1023659 rs334146 0.510.289879478 0.3564 hCV1841983 rs5937 hCV1023661 rs334143 0.510.289879478 0.3543 hCV1841983 rs5937 hCV1023665 rs334138 0.510.289879478 0.3395 hCV1841983 rs5937 hCV1023666 rs334137 0.510.289879478 0.4012 hCV1841983 rs5937 hCV1023669 rs1075774 0.510.289879478 0.3374 hCV1841983 rs5937 hCV11263777 rs11683986 0.510.289879478 0.8536 hCV1841983 rs5937 hCV11263778 rs6749002 0.510.289879478 0.3378 hCV1841983 rs5937 hCV11263786 rs13408910 0.510.289879478 0.4521 hCV1841983 rs5937 hCV11266746 rs6753288 0.510.289879478 0.5815 hCV1841983 rs5937 hCV11266765 rs11679414 0.510.289879478 0.6966 hCV1841983 rs5937 hCV11268771 rs4662718 0.510.289879478 0.7374 hCV1841983 rs5937 hCV12046142 rs334152 0.510.289879478 0.3564 hCV1841983 rs5937 hCV12046143 rs334156 0.510.289879478 0.3564 hCV1841983 rs5937 hCV12046144 rs334158 0.510.289879478 0.3788 hCV1841983 rs5937 hCV12046224 rs10850 0.510.289879478 0.7374 hCV1841983 rs5937 hCV12047693 rs1864552 0.510.289879478 0.3779 hCV1841983 rs5937 hCV1441133 rs7568070 0.510.289879478 0.3758 hCV1841983 rs5937 hCV1441173 rs4536600 0.510.289879478 0.7198 hCV1841983 rs5937 hCV1441189 rs4150499 0.510.289879478 0.605 hCV1841983 rs5937 hCV1441196 rs4150474 0.510.289879478 0.6229 hCV1841983 rs5937 hCV15860236 rs2069904 0.510.289879478 0.9367 hCV1841983 rs5937 hCV15917574 rs2679409 0.510.289879478 0.3564 hCV1841983 rs5937 hCV16241157 rs2460106 0.510.289879478 0.3564 hCV1841983 rs5937 hCV169044 rs11691088 0.510.289879478 0.704 hCV1841983 rs5937 hCV1721256 rs2069910 0.510.289879478 0.3227 hCV1841983 rs5937 hCV1841975 rs1799810 0.510.289879478 0.6119 hCV1841983 rs5937 hCV25630050 rs3732209 0.510.289879478 0.7933 hCV1841983 rs5937 hCV25960135 rs4150402 0.510.289879478 0.7374 hCV1841983 rs5937 hCV25971425 rs4662741 0.510.289879478 0.3564 hCV1841983 rs5937 hCV25993019 rs11673952 0.510.289879478 0.3564 hCV1841983 rs5937 hCV26980926 rs4150471 0.510.289879478 0.6251 hCV1841983 rs5937 hCV27271075 rs2163348 0.510.289879478 0.3793 hCV1841983 rs5937 hCV273435 rs7607907 0.510.289879478 0.7374 hCV1841983 rs5937 hCV27964958 rs4662713 0.510.289879478 0.7178 hCV1841983 rs5937 hCV28026949 rs4662720 0.510.289879478 0.7374 hCV1841983 rs5937 hCV28952331 rs6755028 0.510.289879478 0.7962 hCV1841983 rs5937 hCV28952333 rs6754772 0.510.289879478 0.3767 hCV1841983 rs5937 hCV28955091 rs7567389 0.510.289879478 0.4991 hCV1841983 rs5937 hCV28955092 rs6430936 0.510.289879478 0.7189 hCV1841983 rs5937 hCV28966787 rs7585314 0.510.289879478 0.5885 hCV1841983 rs5937 hCV29404615 rs6709113 0.510.289879478 0.3311 hCV1841983 rs5937 hCV29404616 rs6706077 0.510.289879478 0.3564 hCV1841983 rs5937 hCV29404621 rs7600934 0.510.289879478 0.3564 hCV1841983 rs5937 hCV29404688 rs7582598 0.510.289879478 0.365 hCV1841983 rs5937 hCV29570359 rs6738690 0.510.289879478 0.6251 hCV1841983 rs5937 hCV29636350 rs10496661 0.510.289879478 0.7374 hCV1841983 rs5937 hCV30166207 rs7590030 0.510.289879478 0.7933 hCV1841983 rs5937 hCV30418053 rs6757492 0.510.289879478 0.6961 hCV1841983 rs5937 hCV30598525 rs7556675 0.510.289879478 0.7374 hCV1841983 rs5937 hCV30711743 rs11890243 0.510.289879478 0.5169 hCV1841983 rs5937 hCV31814195 rs11680949 0.510.289879478 0.6251 hCV1841983 rs5937 hCV31814218 rs6430938 0.510.289879478 0.8723 hCV1841983 rs5937 hCV3212726 rs12621149 0.510.289879478 0.292 hCV1841983 rs5937 hCV822512 rs334144 0.51 0.2898794780.3564 hCV1841983 rs5937 hCV8806682 rs1011019 0.51 0.289879478 0.7374hCV1841983 rs5937 hCV8807983 rs1504136 0.51 0.289879478 0.6258hCV1841983 rs5937 hCV8807993 rs1473623 0.51 0.289879478 0.7761hCV1841983 rs5937 hCV8808000 rs891514 0.51 0.289879478 0.3564 hCV1841983rs5937 hCV8810479 rs1604817 0.51 0.289879478 0.6728 hCV1841983 rs5937hCV8810750 rs1158867 0.51 0.289879478 0.6851 hCV1841983 rs5937hCV8836422 rs777554 0.51 0.289879478 0.3932 hCV1841983 rs5937 hCV8837013rs1019842 0.51 0.289879478 0.3723 hCV1841983 rs5937 hCV8837014 rs7775690.51 0.289879478 0.3564 hCV1841983 rs5937 hCV9465822 rs11683427 0.510.289879478 0.4044 hCV1841983 rs5937 hCV9468542 rs7599210 0.510.289879478 0.5771 hCV1841983 rs5937 hDV70929450 rs17261845 0.510.289879478 0.2956 hCV1841983 rs5937 hDV70929452 rs17261859 0.510.289879478 0.2956 hCV1841983 rs5937 hDV75209985 rs2069898 0.510.289879478 0.8713 hCV1859855 rs2291260 hCV12052839 rs8021 0.510.469041298 0.5002 hCV1859855 rs2291260 hCV16089184 rs2873193 0.510.469041298 0.6229 hCV1859855 rs2291260 hCV16174004 rs2242291 0.510.469041298 0.6816 hCV1859855 rs2291260 hCV1859872 rs4758905 0.510.469041298 0.6816 hCV1859855 rs2291260 hCV1859912 rs12303977 0.510.469041298 0.6816 hCV1859855 rs2291260 hCV1859941 rs2306541 0.510.469041298 0.637 hCV1859855 rs2291260 hCV1859948 rs7297261 0.510.469041298 0.5354 hCV1859855 rs2291260 hCV1859956 rs7969859 0.510.469041298 0.6554 hCV1859855 rs2291260 hCV1859996 rs12815354 0.510.469041298 0.5246 hCV1859855 rs2291260 hCV1859997 rs12815207 0.510.469041298 0.5308 hCV1859855 rs2291260 hCV25761477 rs3741490 0.510.469041298 0.637 hCV1859855 rs2291260 hCV27522090 rs3825109 0.510.469041298 0.6918 hCV1859855 rs2291260 hCV27964264 rs4758939 0.510.469041298 0.6816 hCV1859855 rs2291260 hCV30960162 rs11147095 0.510.469041298 0.6816 hCV1859855 rs2291260 hCV31631014 rs12811327 0.510.469041298 0.5728 hCV1952126 rs7223784 hCV11626701 rs1032070 0.510.792412162 0.9128 hCV1952126 rs7223784 hCV27485323 rs3785897 0.510.792412162 0.8875 hCV1952126 rs7223784 hCV2769165 rs2071046 0.510.792412162 0.9129 hCV1952126 rs7223784 hCV2977462 rs4793099 0.510.792412162 0.9128 hCV1952126 rs7223784 hCV3140239 rs36023314 0.510.792412162 0.8867 hCV1952126 rs7223784 hCV3140264 rs6503704 0.510.792412162 1 hCV1952126 rs7223784 hCV31652022 rs12948909 0.510.792412162 1 hCV1952126 rs7223784 hCV31652026 rs11871801 0.510.792412162 1 hCV1952126 rs7223784 hCV587962 rs647397 0.51 0.7924121620.8421 hCV22272267 rs3733402 hCV11786147 rs4862662 0.51 0.0930862440.352 hCV22272267 rs3733402 hCV11786203 rs4253251 0.51 0.0930862440.2672 hCV22272267 rs3733402 hCV11786258 rs4253303 0.51 0.0930862440.5632 hCV22272267 rs3733402 hCV11786259 rs4253304 0.51 0.0930862440.6456 hCV22272267 rs3733402 hCV11786295 rs4253421 0.51 0.0930862440.1162 hCV22272267 rs3733402 hCV11786327 rs13133050 0.51 0.0930862440.2482 hCV22272267 rs3733402 hCV12066118 rs2048 0.51 0.093086244 1hCV22272267 rs3733402 hCV12066119 rs1912826 0.51 0.093086244 0.9284hCV22272267 rs3733402 hCV12066124 rs2036914 0.51 0.093086244 0.3605hCV22272267 rs3733402 hCV12066129 rs1593 0.51 0.093086244 0.1325hCV22272267 rs3733402 hCV1332991 rs11723770 0.51 0.093086244 0.1232hCV22272267 rs3733402 hCV1332992 rs12506228 0.51 0.093086244 0.1088hCV22272267 rs3733402 hCV15793897 rs3087505 0.51 0.093086244 0.12hCV22272267 rs3733402 hCV15811716 rs2102575 0.51 0.093086244 0.1089hCV22272267 rs3733402 hCV15968025 rs2292425 0.51 0.093086244 0.18hCV22272267 rs3733402 hCV15968026 rs2292426 0.51 0.093086244 0.2195hCV22272267 rs3733402 hCV15968034 rs2292428 0.51 0.093086244 0.3058hCV22272267 rs3733402 hCV15968043 rs2292423 0.51 0.093086244 0.6588hCV22272267 rs3733402 hCV15975109 rs2304596 0.51 0.093086244 0.24hCV22272267 rs3733402 hCV2103337 rs13102931 0.51 0.093086244 0.1025hCV22272267 rs3733402 hCV2103343 rs4241824 0.51 0.093086244 0.3019hCV22272267 rs3733402 hCV2103391 rs1008728 0.51 0.093086244 0.2065hCV22272267 rs3733402 hCV2103392 rs12500826 0.51 0.093086244 0.1775hCV22272267 rs3733402 hCV22271609 rs4253326 0.51 0.093086244 0.2299hCV22272267 rs3733402 hCV25474413 rs3822057 0.51 0.093086244 0.312hCV22272267 rs3733402 hCV25474414 rs4253399 0.51 0.093086244 0.1628hCV22272267 rs3733402 hCV25634763 rs4253241 0.51 0.093086244 0.1188hCV22272267 rs3733402 hCV25634781 rs4253299 0.51 0.093086244 0.2584hCV22272267 rs3733402 hCV25989001 hCV25989001 0.51 0.093086244 0.2535hCV22272267 rs3733402 hCV25990131 rs13146272 0.51 0.093086244 0.1915hCV22272267 rs3733402 hCV26265197 rs10014399 0.51 0.093086244 0.2641hCV22272267 rs3733402 hCV26265199 rs2221843 0.51 0.093086244 0.2584hCV22272267 rs3733402 hCV26265231 rs7684025 0.51 0.093086244 0.3837hCV22272267 rs3733402 hCV27473099 rs3733403 0.51 0.093086244 0.1386hCV22272267 rs3733402 hCV27477533 rs3756008 0.51 0.093086244 0.1577hCV22272267 rs3733402 hCV27482765 rs3775301 0.51 0.093086244 0.24hCV22272267 rs3733402 hCV27482766 rs3775302 0.51 0.093086244 0.1546hCV22272267 rs3733402 hCV27506149 rs3822055 0.51 0.093086244 0.2584hCV22272267 rs3733402 hCV27521729 rs3822056 0.51 0.093086244 0.1313hCV22272267 rs3733402 hCV27902808 rs4253236 0.51 0.093086244 0.6716hCV22272267 rs3733402 hCV29053264 rs7667777 0.51 0.093086244 0.3951hCV22272267 rs3733402 hCV29053265 rs4253244 0.51 0.093086244 0.6414hCV22272267 rs3733402 hCV29718000 rs4253238 0.51 0.093086244 1hCV22272267 rs3733402 hCV29826351 rs10025990 0.51 0.093086244 0.1333hCV22272267 rs3733402 hCV29877725 rs4253295 0.51 0.093086244 0.5775hCV22272267 rs3733402 hCV30983907 rs4253246 0.51 0.093086244 0.1188hCV22272267 rs3733402 hCV32209636 rs11132387 0.51 0.093086244 0.1446hCV22272267 rs3733402 hCV32291217 rs4253323 0.51 0.093086244 0.24hCV22272267 rs3733402 hCV32291269 rs4253417 0.51 0.093086244 0.1165hCV22272267 rs3733402 hCV32291286 rs4253422 0.51 0.093086244 0.168hCV22272267 rs3733402 hCV32291287 rs4253423 0.51 0.093086244 0.168hCV22272267 rs3733402 hCV32291295 rs4253292 0.51 0.093086244 0.2444hCV22272267 rs3733402 hCV32291301 rs4253302 0.51 0.093086244 0.2397hCV22272267 rs3733402 hCV32295028 rs4253260 0.51 0.093086244 0.24hCV22272267 rs3733402 hCV3229991 rs4241815 0.51 0.093086244 1hCV22272267 rs3733402 hCV3229992 rs3775298 0.51 0.093086244 1hCV22272267 rs3733402 hCV3229995 rs11132382 0.51 0.093086244 1hCV22272267 rs3733402 hCV3230000 rs4253294 0.51 0.093086244 0.4581hCV22272267 rs3733402 hCV3230001 rs4253296 0.51 0.093086244 0.1188hCV22272267 rs3733402 hCV3230002 rs4253297 0.51 0.093086244 0.5815hCV22272267 rs3733402 hCV3230003 rs2304595 0.51 0.093086244 0.6471hCV22272267 rs3733402 hCV3230004 rs4253301 0.51 0.093086244 0.1089hCV22272267 rs3733402 hCV3230006 rs4253308 0.51 0.093086244 0.5775hCV22272267 rs3733402 hCV3230007 rs4253311 0.51 0.093086244 1hCV22272267 rs3733402 hCV3230010 rs4253315 0.51 0.093086244 0.1137hCV22272267 rs3733402 hCV3230011 rs4253320 0.51 0.093086244 0.5815hCV22272267 rs3733402 hCV3230012 rs4241821 0.51 0.093086244 0.2584hCV22272267 rs3733402 hCV3230013 rs3775303 0.51 0.093086244 0.6456hCV22272267 rs3733402 hCV3230014 rs4861709 0.51 0.093086244 0.4581hCV22272267 rs3733402 hCV3230016 rs4253325 0.51 0.093086244 0.112hCV22272267 rs3733402 hCV3230017 rs4253327 0.51 0.093086244 0.1008hCV22272267 rs3733402 hCV3230018 rs925453 0.51 0.093086244 0.4359hCV22272267 rs3733402 hCV3230019 rs4253332 0.51 0.093086244 0.4359hCV22272267 rs3733402 hCV3230025 rs3756009 0.51 0.093086244 0.149hCV22272267 rs3733402 hCV3230031 rs4253419 0.51 0.093086244 0.168hCV22272267 rs3733402 hCV3230038 rs2289252 0.51 0.093086244 0.1192hCV22272267 rs3733402 hCV3230083 rs10013653 0.51 0.093086244 0.3018hCV22272267 rs3733402 hCV3230084 rs7682918 0.51 0.093086244 0.2829hCV22272267 rs3733402 hCV3230094 rs7687818 0.51 0.093086244 0.4367hCV22272267 rs3733402 hCV3230096 rs3817184 0.51 0.093086244 0.3722hCV22272267 rs3733402 hCV3230097 rs3736455 0.51 0.093086244 0.2406hCV22272267 rs3733402 hCV3230101 rs6835839 0.51 0.093086244 0.3515hCV22272267 rs3733402 hCV3230106 rs1473597 0.51 0.093086244 0.318hCV22272267 rs3733402 hCV3230110 rs2276917 0.51 0.093086244 0.3058hCV22272267 rs3733402 hCV3230113 rs1053094 0.51 0.093086244 0.5831hCV22272267 rs3733402 hCV3230118 rs4253429 0.51 0.093086244 0.168hCV22272267 rs3733402 hCV3230125 rs11938564 0.51 0.093086244 0.1034hCV22272267 rs3733402 hCV3230136 rs13116273 0.51 0.093086244 0.0947hCV22272267 rs3733402 hCV32313006 rs4253248 0.51 0.093086244 1hCV22272267 rs3733402 hCV32313024 rs4253239 0.51 0.093086244 0.2444hCV22272267 rs3733402 hCV32358975 rs4253255 0.51 0.093086244 1hCV22272267 rs3733402 hCV32358984 rs4253256 0.51 0.093086244 0.6645hCV22272267 rs3733402 hCV7750713 rs4862596 0.51 0.093086244 0.1067hCV22272267 rs3733402 hCV7750737 rs13140248 0.51 0.093086244 0.1031hCV22272267 rs3733402 hCV8241630 rs925451 0.51 0.093086244 0.1476hCV22272267 rs3733402 hCV8241631 rs1511802 0.51 0.093086244 0.5775hCV22272267 rs3733402 hCV8241632 rs1511801 0.51 0.093086244 1hCV22272267 rs3733402 hDV68550952 rs4253289 0.51 0.093086244 0.102hCV22272267 rs3733402 hDV71222711 rs4253252 0.51 0.093086244 1hCV22273419 rs2304167 hCV11977629 rs1654459 0.51 0.488273752 0.5665hCV22273419 rs2304167 hCV1376257 rs10416380 0.51 0.488273752 0.9727hCV22273419 rs2304167 hCV1376262 rs1671150 0.51 0.488273752 1hCV22273419 rs2304167 hCV1376264 rs1671151 0.51 0.488273752 1hCV22273419 rs2304167 hCV1376265 rs1671152 0.51 0.488273752 0.8131hCV22273419 rs2304167 hCV1376266 rs1654413 0.51 0.488273752 1hCV22273419 rs2304167 hCV1376342 rs1654416 0.51 0.488273752 0.9724hCV22273419 rs2304167 hCV1376359 rs2886412 0.51 0.488273752 1hCV22273419 rs2304167 hCV16044361 rs2569513 0.51 0.488273752 0.639hCV22273419 rs2304167 hCV26895244 rs1671153 0.51 0.488273752 1hCV22273419 rs2304167 hCV26895257 rs2886415 0.51 0.488273752 1hCV22273419 rs2304167 hCV29271569 rs1626971 0.51 0.488273752 0.7325hCV22273419 rs2304167 hCV31722831 rs11671922 0.51 0.488273752 1hCV22273419 rs2304167 hCV31722832 rs11084381 0.51 0.488273752 0.8942hCV22273419 rs2304167 hCV31722834 rs11084382 0.51 0.488273752 0.783hCV22273419 rs2304167 hCV31722835 rs11668169 0.51 0.488273752 0.8939hCV22273419 rs2304167 hCV31722836 rs11672026 0.51 0.488273752 0.8884hCV22273419 rs2304167 hCV7841075 rs1671196 0.51 0.488273752 0.8942hCV22273419 rs2304167 hCV8703249 rs1654444 0.51 0.488273752 0.633hCV22273419 rs2304167 hCV8717752 rs1671217 0.51 0.488273752 0.7325hCV22273419 rs2304167 hCV8717761 rs1654439 0.51 0.488273752 0.5719hCV22273419 rs2304167 hCV8717793 rs1654433 0.51 0.488273752 0.639hCV22273419 rs2304167 hCV8717794 rs1654432 0.51 0.488273752 0.639hCV22273419 rs2304167 hCV8717845 rs892090 0.51 0.488273752 0.7101hCV22273419 rs2304167 hCV8717846 rs892089 0.51 0.488273752 1 hCV22273419rs2304167 hCV8717871 rs1654421 0.51 0.488273752 0.754 hCV22273419rs2304167 hCV8717873 rs1613662 0.51 0.488273752 0.7101 hCV22273419rs2304167 hCV8717881 rs1654420 0.51 0.488273752 0.8939 hCV22273419rs2304167 hCV8717893 rs1671192 0.51 0.488273752 1 hCV22273419 rs2304167hCV8718961 rs1654451 0.51 0.488273752 0.5646 hCV22273419 rs2304167hCV8718972 rs1654447 0.51 0.488273752 0.6147 hCV22273419 rs2304167hCV9490926 rs1654419 0.51 0.488273752 0.8939 hCV2303891 rs1801690hCV2658414 rs8178851 0.51 0.431588444 0.7358 hCV2303891 rs1801690hCV2658416 rs8178853 0.51 0.431588444 0.7358 hCV2303891 rs1801690hCV2658437 rs11651658 0.51 0.431588444 0.858 hCV2303891 rs1801690hCV2658444 rs7209242 0.51 0.431588444 0.497 hCV2303891 rs1801690hCV2658455 rs11658189 0.51 0.431588444 0.9185 hCV2303891 rs1801690hCV26589423 rs1014399 0.51 0.431588444 0.574 hCV2303891 rs1801690hCV27842286 rs8178822 0.51 0.431588444 0.778 hCV2303891 rs1801690hCV29176910 rs7211380 0.51 0.431588444 0.7358 hCV2303891 rs1801690hCV29577360 rs9910950 0.51 0.431588444 0.9185 hCV2303891 rs1801690hCV29866571 rs9891968 0.51 0.431588444 0.8255 hCV2303891 rs1801690hCV29992830 rs8178839 0.51 0.431588444 0.497 hCV2303891 rs1801690hCV30064665 rs9902706 0.51 0.431588444 0.9185 hCV2303891 rs1801690hCV30082731 rs8178838 0.51 0.431588444 0.8247 hCV2303891 rs1801690hCV30118779 rs8178841 0.51 0.431588444 0.778 hCV2303891 rs1801690hCV30298770 rs8178842 0.51 0.431588444 0.7215 hCV2303891 rs1801690hCV30352818 rs8178847 0.51 0.431588444 0.778 hCV2303891 rs1801690hCV30443106 rs7213041 0.51 0.431588444 0.778 hCV2303891 rs1801690hCV30551147 rs9908597 0.51 0.431588444 0.8255 hCV2303891 rs1801690hCV31400900 rs7216660 0.51 0.431588444 0.9185 hCV2303891 rs1801690hDV70764335 rs16958979 0.51 0.431588444 0.7777 hCV2303891 rs1801690hDV70764357 rs16959006 0.51 0.431588444 1 hCV233148 rs1417121hCV12073836 rs1008173 0.51 0.233111365 0.4803 hCV233148 rs1417121hCV12073840 rs14403 0.51 0.233111365 0.8606 hCV233148 rs1417121hCV15760229 rs3006939 0.51 0.233111365 0.6414 hCV233148 rs1417121hCV15760238 rs3006936 0.51 0.233111365 0.6656 hCV233148 rs1417121hCV15760239 rs3006923 0.51 0.233111365 0.7633 hCV233148 rs1417121hCV15760280 rs3006940 0.51 0.233111365 0.6414 hCV233148 rs1417121hCV15823024 rs2125230 0.51 0.233111365 0.4131 hCV233148 rs1417121hCV15885425 rs2290754 0.51 0.233111365 0.4131 hCV233148 rs1417121hCV15953071 rs2953329 0.51 0.233111365 0.238 hCV233148 rs1417121hCV15965338 rs2291410 0.51 0.233111365 0.4485 hCV233148 rs1417121hCV16082410 rs2881275 0.51 0.233111365 0.4499 hCV233148 rs1417121hCV16189408 rs2994320 0.51 0.233111365 0.4425 hCV233148 rs1417121hCV1678656 rs1458024 0.51 0.233111365 0.4499 hCV233148 rs1417121hCV1678674 rs1458023 0.51 0.233111365 0.4131 hCV233148 rs1417121hCV1678687 rs320305 0.51 0.233111365 0.3115 hCV233148 rs1417121hCV26034142 rs9428576 0.51 0.233111365 0.4375 hCV233148 rs1417121hCV26034157 rs2994329 0.51 0.233111365 0.4814 hCV233148 rs1417121hCV26034158 rs4515770 0.51 0.233111365 0.6414 hCV233148 rs1417121hCV26034160 rs2994327 0.51 0.233111365 0.7257 hCV233148 rs1417121hCV26338482 rs10803143 0.51 0.233111365 0.2626 hCV233148 rs1417121hCV26338512 rs2994339 0.51 0.233111365 0.4425 hCV233148 rs1417121hCV26338513 rs3006917 0.51 0.233111365 0.4425 hCV233148 rs1417121hCV26719082 rs10927046 0.51 0.233111365 0.3102 hCV233148 rs1417121hCV26719085 rs10927047 0.51 0.233111365 0.3441 hCV233148 rs1417121hCV26719107 rs7538011 0.51 0.233111365 0.3776 hCV233148 rs1417121hCV26719108 rs10927035 0.51 0.233111365 0.2612 hCV233148 rs1417121hCV26719113 rs7517340 0.51 0.233111365 0.3991 hCV233148 rs1417121hCV26719116 rs10927039 0.51 0.233111365 0.49 hCV233148 rs1417121hCV26719120 rs10927040 0.51 0.233111365 0.4485 hCV233148 rs1417121hCV26719121 rs10927041 0.51 0.233111365 0.4485 hCV233148 rs1417121hCV26719149 rs6675851 0.51 0.233111365 0.4131 hCV233148 rs1417121hCV26719162 rs4132509 0.51 0.233111365 0.4131 hCV233148 rs1417121hCV26719176 rs10927076 0.51 0.233111365 0.4131 hCV233148 rs1417121hCV26719192 rs10803161 0.51 0.233111365 0.4774 hCV233148 rs1417121hCV26719201 rs4478795 0.51 0.233111365 0.2532 hCV233148 rs1417121hCV26719219 rs9782958 0.51 0.233111365 0.4131 hCV233148 rs1417121hCV26719222 rs4553169 0.51 0.233111365 0.4131 hCV233148 rs1417121hCV26719227 rs10927065 0.51 0.233111365 0.3115 hCV233148 rs1417121hCV26719232 rs10803158 0.51 0.233111365 0.4131 hCV233148 rs1417121hCV26719233 rs10927067 0.51 0.233111365 0.4131 hCV233148 rs1417121hCV27498250 rs3766673 0.51 0.233111365 0.4485 hCV233148 rs1417121hCV29210363 rs6656918 0.51 0.233111365 0.6414 hCV233148 rs1417121hCV29542869 rs7534117 0.51 0.233111365 0.4131 hCV233148 rs1417121hCV29560960 rs7519673 0.51 0.233111365 0.3115 hCV233148 rs1417121hCV29741723 rs7517921 0.51 0.233111365 0.3711 hCV233148 rs1417121hCV29994467 rs6694738 0.51 0.233111365 0.3776 hCV233148 rs1417121hCV30084348 rs9287269 0.51 0.233111365 0.4111 hCV233148 rs1417121hCV30372886 rs9782883 0.51 0.233111365 0.4131 hCV233148 rs1417121hCV30382231 rs9428966 0.51 0.233111365 1 hCV233148 rs1417121 hCV30690777rs12045585 0.51 0.233111365 0.3015 hCV233148 rs1417121 hCV30690778rs12140414 0.51 0.233111365 0.5616 hCV233148 rs1417121 hCV30690780rs10737888 0.51 0.233111365 0.6414 hCV233148 rs1417121 hCV30690784rs4658574 0.51 0.233111365 0.7257 hCV233148 rs1417121 hCV31056133rs10927006 0.51 0.233111365 0.2564 hCV233148 rs1417121 hCV31056162rs12049318 0.51 0.233111365 0.2564 hCV233148 rs1417121 hCV31523557rs10754807 0.51 0.233111365 0.4131 hCV233148 rs1417121 hCV31523563rs10927051 0.51 0.233111365 0.4633 hCV233148 rs1417121 hCV31523638rs12037013 0.51 0.233111365 0.3441 hCV233148 rs1417121 hCV31523639rs12034588 0.51 0.233111365 0.4326 hCV233148 rs1417121 hCV31523643rs6671475 0.51 0.233111365 0.4485 hCV233148 rs1417121 hCV31523650rs12048930 0.51 0.233111365 0.3711 hCV233148 rs1417121 hCV31523658rs12047209 0.51 0.233111365 0.317 hCV233148 rs1417121 hCV31523688rs12049228 0.51 0.233111365 0.4351 hCV233148 rs1417121 hCV31523691rs12021907 0.51 0.233111365 0.3115 hCV233148 rs1417121 hCV31523707rs10803152 0.51 0.233111365 0.3441 hCV233148 rs1417121 hCV31523710rs10927059 0.51 0.233111365 0.4131 hCV233148 rs1417121 hCV31523723rs12140040 0.51 0.233111365 0.3202 hCV233148 rs1417121 hCV31523736rs12124113 0.51 0.233111365 0.3115 hCV233148 rs1417121 hCV31523740rs12032342 0.51 0.233111365 0.4499 hCV233148 rs1417121 hCV31523744rs12031994 0.51 0.233111365 0.3115 hCV233148 rs1417121 hCV804126rs320320 0.51 0.233111365 0.4499 hCV233148 rs1417121 hCV8688079 rs8848080.51 0.233111365 0.7257 hCV233148 rs1417121 hCV8688080 rs884328 0.510.233111365 0.7257 hCV233148 rs1417121 hCV8688111 rs1578275 0.510.233111365 0.5616 hCV233148 rs1417121 hCV9493073 rs1058305 0.510.233111365 1 hCV233148 rs1417121 hCV9493081 rs1058304 0.51 0.2331113651 hCV233148 rs1417121 hCV97631 rs1538773 0.51 0.233111365 0.6414hCV233148 rs1417121 hDV71836703 rs6429433 0.51 0.233111365 0.4157hCV233148 rs1417121 hDV90784784 rs320339 0.51 0.233111365 0.3409hCV2442143 rs12544854 hCV15753018 rs2299606 0.51 0.805894186 0.9649hCV2442143 rs12544854 hCV15844343 rs2427746 0.51 0.805894186 0.8982hCV2442143 rs12544854 hCV2442136 rs12155668 0.51 0.805894186 1hCV2442143 rs12544854 hCV2442137 rs12155885 0.51 0.805894186 1hCV2442143 rs12544854 hCV2442146 rs966118 0.51 0.805894186 1 hCV2442143rs12544854 hCV2442155 rs3753117 0.51 0.805894186 1 hCV2442143 rs12544854hCV2442156 rs35573135 0.51 0.805894186 0.841 hCV2442143 rs12544854hCV26696706 rs2299607 0.51 0.805894186 1 hCV2442143 rs12544854hCV27474371 rs3753116 0.51 0.805894186 1 hCV2442143 rs12544854hCV31495915 rs3753115 0.51 0.805894186 1 hCV2442143 rs12544854hCV31495928 rs12548139 0.51 0.805894186 1 hCV2442143 rs12544854hCV8947815 rs1049874 0.51 0.805894186 1 hCV2499170 rs169713 hCV2238240rs209773 0.51 0.626344353 0.9402 hCV2499170 rs169713 hCV2238245 rs238050.51 0.626344353 0.8916 hCV2499170 rs169713 hCV2238247 rs209778 0.510.626344353 0.6678 hCV2499170 rs169713 hCV2238250 rs209780 0.510.626344353 0.8809 hCV2499170 rs169713 hCV2238261 rs209814 0.510.626344353 0.6439 hCV2499170 rs169713 hCV2238263 rs209812 0.510.626344353 0.6422 hCV2499170 rs169713 hCV2499165 rs209774 0.510.626344353 1 hCV2499170 rs169713 hCV2499169 rs85219 0.51 0.626344353 1hCV2499170 rs169713 hCV2499176 rs9380643 0.51 0.626344353 0.6493hCV2499170 rs169713 hCV2499198 rs1205883 0.51 0.626344353 0.6439hCV2499170 rs169713 hCV2499199 rs1205884 0.51 0.626344353 0.6439hCV2499170 rs169713 hCV2499201 rs1205887 0.51 0.626344353 0.6439hCV2499170 rs169713 hCV31001553 rs10947661 0.51 0.626344353 0.8779hCV2499170 rs169713 hCV7465311 rs1205863 0.51 0.626344353 0.6439hCV2499170 rs169713 hCV7465312 rs864245 0.51 0.626344353 0.6439hCV2499170 rs169713 hCV7465347 rs1205852 0.51 0.626344353 0.6439hCV2499170 rs169713 hCV7465349 rs1205850 0.51 0.626344353 0.8424hCV2499170 rs169713 hCV7465354 rs1205849 0.51 0.626344353 0.8932hCV2499170 rs169713 hCV7465364 rs864244 0.51 0.626344353 0.9459hCV2499170 rs169713 hCV7465377 rs1210621 0.51 0.626344353 0.9438hCV2499170 rs169713 hCV7465418 rs876828 0.51 0.626344353 0.7396hCV2499170 rs169713 hDV101721202 rs9394412 0.51 0.626344353 0.8779hCV2532034 rs6003 hCV11888484 rs6694672 0.51 0.719447218 0.9425hCV2532034 rs6003 hCV11888496 rs7554757 0.51 0.719447218 1 hCV2532034rs6003 hCV11888533 rs1115247 0.51 0.719447218 1 hCV2532034 rs6003hCV11888556 rs7542397 0.51 0.719447218 1 hCV2532034 rs6003 hCV11888566rs1888991 0.51 0.719447218 0.9451 hCV2532034 rs6003 hCV15832928rs2151133 0.51 0.719447218 0.8803 hCV2532034 rs6003 hCV15832929rs2151134 0.51 0.719447218 1 hCV2532034 rs6003 hCV1648949 rs6692162 0.510.719447218 1 hCV2532034 rs6003 hCV1739697 rs10429911 0.51 0.7194472180.8913 hCV2532034 rs6003 hCV1739698 rs1415217 0.51 0.719447218 0.8913hCV2532034 rs6003 hCV1739699 rs7520503 0.51 0.719447218 0.945 hCV2532034rs6003 hCV1739712 rs510135 0.51 0.719447218 0.8913 hCV2532034 rs6003hCV1742489 rs476390 0.51 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hCV2759693 rs10754215 0.51 0.719447218 1 hCV2532034 rs6003hCV2759696 rs7411719 0.51 0.719447218 1 hCV2532034 rs6003 hCV2759703rs1412640 0.51 0.719447218 1 hCV2532034 rs6003 hCV2759704 rs1953064 0.510.719447218 0.8803 hCV2532034 rs6003 hCV2759709 rs4915313 0.510.719447218 1 hCV2532034 rs6003 hCV2759711 rs4915309 0.51 0.719447218 1hCV2532034 rs6003 hCV2759725 rs6670056 0.51 0.719447218 1 hCV2532034rs6003 hCV27898326 rs4915316 0.51 0.719447218 0.9396 hCV2532034 rs6003hCV27898327 rs4915327 0.51 0.719447218 1 hCV2532034 rs6003 hCV28005188rs4342879 0.51 0.719447218 0.8913 hCV2532034 rs6003 hCV29222813rs4915315 0.51 0.719447218 0.8023 hCV2532034 rs6003 hCV29222814rs6428387 0.51 0.719447218 0.8803 hCV2532034 rs6003 hCV29222817rs6656858 0.51 0.719447218 1 hCV2532034 rs6003 hCV29295007 rs66564480.51 0.719447218 0.88 hCV2532034 rs6003 hCV29491389 rs7513826 0.510.719447218 0.8913 hCV2532034 rs6003 hCV29633649 rs7539642 0.510.719447218 0.8803 hCV2532034 rs6003 hCV29724082 rs9427661 0.510.719447218 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hCV2532034rs6003 hCV87892 rs2336597 0.51 0.719447218 0.9425 hCV2532034 rs6003hCV9114466 rs3891964 0.51 0.719447218 0.9425 hCV2532034 rs6003hCV9114630 rs1576880 0.51 0.719447218 1 hCV2532034 rs6003 hCV9114656rs9427662 0.51 0.719447218 0.9425 hCV2532034 rs6003 hCV9114658rs13376702 0.51 0.719447218 0.7419 hCV25474413 rs3822057 hCV11786147rs4862662 0.51 0.057574841 0.2412 hCV25474413 rs3822057 hCV11786258rs4253303 0.51 0.057574841 0.2622 hCV25474413 rs3822057 hCV11786259rs4253304 0.51 0.057574841 0.2992 hCV25474413 rs3822057 hCV11786295rs4253421 0.51 0.057574841 0.0942 hCV25474413 rs3822057 hCV11786301rs5970 0.51 0.057574841 0.0764 hCV25474413 rs3822057 hCV11786307rs1062547 0.51 0.057574841 0.4723 hCV25474413 rs3822057 hCV11786311rs13145616 0.51 0.057574841 0.0838 hCV25474413 rs3822057 hCV11786327rs13133050 0.51 0.057574841 0.2298 hCV25474413 rs3822057 hCV12066116rs1877320 0.51 0.057574841 0.1289 hCV25474413 rs3822057 hCV12066118rs2048 0.51 0.057574841 0.3088 hCV25474413 rs3822057 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hCV27482765rs3775301 0.51 0.057574841 0.0626 hCV25474413 rs3822057 hCV27490984rs3822058 0.51 0.057574841 0.477 hCV25474413 rs3822057 hCV27521729rs3822056 0.51 0.057574841 0.1222 hCV25474413 rs3822057 hCV27902803rs4862665 0.51 0.057574841 0.0873 hCV25474413 rs3822057 hCV27902808rs4253236 0.51 0.057574841 0.1514 hCV25474413 rs3822057 hCV28960679rs6844764 0.51 0.057574841 0.1108 hCV25474413 rs3822057 hCV29053261rs6842047 0.51 0.057574841 0.1042 hCV25474413 rs3822057 hCV29053264rs7667777 0.51 0.057574841 0.2192 hCV25474413 rs3822057 hCV29053265rs4253244 0.51 0.057574841 0.1369 hCV25474413 rs3822057 hCV29640635rs10029715 0.51 0.057574841 0.0904 hCV25474413 rs3822057 hCV29718000rs4253238 0.51 0.057574841 0.3736 hCV25474413 rs3822057 hCV29826351rs10025990 0.51 0.057574841 0.1507 hCV25474413 rs3822057 hCV29877725rs4253295 0.51 0.057574841 0.2932 hCV25474413 rs3822057 hCV30307525rs10025152 0.51 0.057574841 0.0904 hCV25474413 rs3822057 hCV30492573rs10471184 0.51 0.057574841 0.1042 hCV25474413 rs3822057 hCV30562347rs4253418 0.51 0.057574841 0.0597 hCV25474413 rs3822057 hCV30983902rs4862668 0.51 0.057574841 0.1289 hCV25474413 rs3822057 hCV30983907rs4253246 0.51 0.057574841 0.0739 hCV25474413 rs3822057 hCV30983927rs6552962 0.51 0.057574841 0.0626 hCV25474413 rs3822057 hCV32209629rs12715865 0.51 0.057574841 0.1687 hCV25474413 rs3822057 hCV32209636rs11132387 0.51 0.057574841 0.4496 hCV25474413 rs3822057 hCV32209637rs13143773 0.51 0.057574841 0.302 hCV25474413 rs3822057 hCV32209638rs12507040 0.51 0.057574841 0.3609 hCV25474413 rs3822057 hCV32291217rs4253323 0.51 0.057574841 0.0626 hCV25474413 rs3822057 hCV32291256rs4253406 0.51 0.057574841 0.0668 hCV25474413 rs3822057 hCV32291269rs4253417 0.51 0.057574841 0.419 hCV25474413 rs3822057 hCV32291286rs4253422 0.51 0.057574841 0.2386 hCV25474413 rs3822057 hCV32291287rs4253423 0.51 0.057574841 0.2386 hCV25474413 rs3822057 hCV32291295rs4253292 0.51 0.057574841 0.1106 hCV25474413 rs3822057 hCV32291301rs4253302 0.51 0.057574841 0.0583 hCV25474413 rs3822057 hCV32295028rs4253260 0.51 0.057574841 0.0626 hCV25474413 rs3822057 hCV3229991rs4241815 0.51 0.057574841 0.312 hCV25474413 rs3822057 hCV3229992rs3775298 0.51 0.057574841 0.312 hCV25474413 rs3822057 hCV3229995rs11132382 0.51 0.057574841 0.3554 hCV25474413 rs3822057 hCV3230000rs4253294 0.51 0.057574841 0.1258 hCV25474413 rs3822057 hCV3230001rs4253296 0.51 0.057574841 0.0739 hCV25474413 rs3822057 hCV3230002rs4253297 0.51 0.057574841 0.2517 hCV25474413 rs3822057 hCV3230003rs2304595 0.51 0.057574841 0.3609 hCV25474413 rs3822057 hCV3230004rs4253301 0.51 0.057574841 0.0995 hCV25474413 rs3822057 hCV3230006rs4253308 0.51 0.057574841 0.2932 hCV25474413 rs3822057 hCV3230007rs4253311 0.51 0.057574841 0.312 hCV25474413 rs3822057 hCV3230011rs4253320 0.51 0.057574841 0.2517 hCV25474413 rs3822057 hCV3230013rs3775303 0.51 0.057574841 0.2992 hCV25474413 rs3822057 hCV3230014rs4861709 0.51 0.057574841 0.1258 hCV25474413 rs3822057 hCV3230017rs4253327 0.51 0.057574841 0.0594 hCV25474413 rs3822057 hCV3230018rs925453 0.51 0.057574841 0.1356 hCV25474413 rs3822057 hCV3230019rs4253332 0.51 0.057574841 0.1286 hCV25474413 rs3822057 hCV3230021rs13135645 0.51 0.057574841 0.1443 hCV25474413 rs3822057 hCV3230022rs11132383 0.51 0.057574841 0.1929 hCV25474413 rs3822057 hCV3230025rs3756009 0.51 0.057574841 0.6037 hCV25474413 rs3822057 hCV3230030rs4253408 0.51 0.057574841 0.0716 hCV25474413 rs3822057 hCV3230031rs4253419 0.51 0.057574841 0.2386 hCV25474413 rs3822057 hCV3230032rs5974 0.51 0.057574841 0.0838 hCV25474413 rs3822057 hCV3230038rs2289252 0.51 0.057574841 0.4122 hCV25474413 rs3822057 hCV3230083rs10013653 0.51 0.057574841 0.3369 hCV25474413 rs3822057 hCV3230084rs7682918 0.51 0.057574841 0.2521 hCV25474413 rs3822057 hCV3230094rs7687818 0.51 0.057574841 0.3057 hCV25474413 rs3822057 hCV3230096rs3817184 0.51 0.057574841 0.2412 hCV25474413 rs3822057 hCV3230097rs3736455 0.51 0.057574841 0.2152 hCV25474413 rs3822057 hCV3230101rs6835839 0.51 0.057574841 0.0843 hCV25474413 rs3822057 hCV3230106rs1473597 0.51 0.057574841 0.1509 hCV25474413 rs3822057 hCV3230110rs2276917 0.51 0.057574841 0.1608 hCV25474413 rs3822057 hCV3230113rs1053094 0.51 0.057574841 0.2648 hCV25474413 rs3822057 hCV3230118rs4253429 0.51 0.057574841 0.2386 hCV25474413 rs3822057 hCV3230119rs4253430 0.51 0.057574841 0.4654 hCV25474413 rs3822057 hCV3230121rs4253431 0.51 0.057574841 0.0838 hCV25474413 rs3822057 hCV3230125rs11938564 0.51 0.057574841 0.2911 hCV25474413 rs3822057 hCV3230131rs13136269 0.51 0.057574841 0.3609 hCV25474413 rs3822057 hCV3230133rs12511874 0.51 0.057574841 0.3083 hCV25474413 rs3822057 hCV3230134rs12500151 0.51 0.057574841 0.3453 hCV25474413 rs3822057 hCV3230136rs13116273 0.51 0.057574841 0.3534 hCV25474413 rs3822057 hCV32313006rs4253248 0.51 0.057574841 0.3617 hCV25474413 rs3822057 hCV32313007rs4862666 0.51 0.057574841 0.0873 hCV25474413 rs3822057 hCV32313024rs4253239 0.51 0.057574841 0.1106 hCV25474413 rs3822057 hCV32358975rs4253255 0.51 0.057574841 0.2992 hCV25474413 rs3822057 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hCV263841 rs1523127hCV255886 rs10511394 0.51 0.401557164 0.569 hCV263841 rs1523127hCV27504984 rs3814055 0.51 0.401557164 1 hCV263841 rs1523127 hCV278948rs1464599 0.51 0.401557164 0.569 hCV263841 rs1523127 hCV29841665rs7623217 0.51 0.401557164 0.5802 hCV263841 rs1523127 hCV30562884rs9815093 0.51 0.401557164 0.4905 hCV263841 rs1523127 hCV30699687rs11711386 0.51 0.401557164 0.4402 hCV263841 rs1523127 hCV30747432rs12488820 0.51 0.401557164 0.9212 hCV263841 rs1523127 hCV9152783rs1523130 0.51 0.401557164 0.9003 hCV27474895 rs3756011 hCV11786147rs4862662 0.51 0.046522553 0.1651 hCV27474895 rs3756011 hCV11786235rs4253287 0.51 0.046522553 0.096 hCV27474895 rs3756011 hCV11786258rs4253303 0.51 0.046522553 0.1518 hCV27474895 rs3756011 hCV11786259rs4253304 0.51 0.046522553 0.2126 hCV27474895 rs3756011 hCV11786295rs4253421 0.51 0.046522553 0.0964 hCV27474895 rs3756011 hCV11786301rs5970 0.51 0.046522553 0.0964 hCV27474895 rs3756011 hCV11786307rs1062547 0.51 0.046522553 0.3474 hCV27474895 rs3756011 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hCV26038139rs4253405 0.51 0.046522553 0.2975 hCV27474895 rs3756011 hCV26265231rs7684025 0.51 0.046522553 0.2227 hCV27474895 rs3756011 hCV27309991rs4572916 0.51 0.046522553 0.1096 hCV27474895 rs3756011 hCV27473099rs3733403 0.51 0.046522553 0.0591 hCV27474895 rs3756011 hCV27477533rs3756008 0.51 0.046522553 0.7565 hCV27474895 rs3756011 hCV27490984rs3822058 0.51 0.046522553 0.3739 hCV27474895 rs3756011 hCV27902803rs4862665 0.51 0.046522553 0.0748 hCV27474895 rs3756011 hCV27902808rs4253236 0.51 0.046522553 0.0489 hCV27474895 rs3756011 hCV28960679rs6844764 0.51 0.046522553 0.1341 hCV27474895 rs3756011 hCV29053261rs6842047 0.51 0.046522553 0.0748 hCV27474895 rs3756011 hCV29053264rs7667777 0.51 0.046522553 0.1527 hCV27474895 rs3756011 hCV29053266rs7687961 0.51 0.046522553 0.0784 hCV27474895 rs3756011 hCV29640635rs10029715 0.51 0.046522553 0.1232 hCV27474895 rs3756011 hCV29718000rs4253238 0.51 0.046522553 0.1192 hCV27474895 rs3756011 hCV29826351rs10025990 0.51 0.046522553 0.078 hCV27474895 rs3756011 hCV29877725rs4253295 0.51 0.046522553 0.2015 hCV27474895 rs3756011 hCV30307525rs10025152 0.51 0.046522553 0.1232 hCV27474895 rs3756011 hCV30492573rs10471184 0.51 0.046522553 0.0748 hCV27474895 rs3756011 hCV30562347rs4253418 0.51 0.046522553 0.0479 hCV27474895 rs3756011 hCV30983902rs4862668 0.51 0.046522553 0.0667 hCV27474895 rs3756011 hCV30983927rs6552962 0.51 0.046522553 0.0811 hCV27474895 rs3756011 hCV32209629rs12715865 0.51 0.046522553 0.1297 hCV27474895 rs3756011 hCV32209635rs6848311 0.51 0.046522553 0.1065 hCV27474895 rs3756011 hCV32209636rs11132387 0.51 0.046522553 0.44 hCV27474895 rs3756011 hCV32209637rs13143773 0.51 0.046522553 0.2103 hCV27474895 rs3756011 hCV32209638rs12507040 0.51 0.046522553 0.2952 hCV27474895 rs3756011 hCV32291256rs4253406 0.51 0.046522553 0.0719 hCV27474895 rs3756011 hCV32291269rs4253417 0.51 0.046522553 0.9279 hCV27474895 rs3756011 hCV32291286rs4253422 0.51 0.046522553 0.1355 hCV27474895 rs3756011 hCV32291287rs4253423 0.51 0.046522553 0.1355 hCV27474895 rs3756011 hCV3229991rs4241815 0.51 0.046522553 0.0893 hCV27474895 rs3756011 hCV3229992rs3775298 0.51 0.046522553 0.0893 hCV27474895 rs3756011 hCV3229995rs11132382 0.51 0.046522553 0.1192 hCV27474895 rs3756011 hCV3230002rs4253297 0.51 0.046522553 0.1602 hCV27474895 rs3756011 hCV3230003rs2304595 0.51 0.046522553 0.2636 hCV27474895 rs3756011 hCV3230006rs4253308 0.51 0.046522553 0.2015 hCV27474895 rs3756011 hCV3230007rs4253311 0.51 0.046522553 0.0893 hCV27474895 rs3756011 hCV3230010rs4253315 0.51 0.046522553 0.0729 hCV27474895 rs3756011 hCV3230011rs4253320 0.51 0.046522553 0.1602 hCV27474895 rs3756011 hCV3230013rs3775303 0.51 0.046522553 0.2126 hCV27474895 rs3756011 hCV3230016rs4253325 0.51 0.046522553 0.0964 hCV27474895 rs3756011 hCV3230017rs4253327 0.51 0.046522553 0.0647 hCV27474895 rs3756011 hCV3230021rs13135645 0.51 0.046522553 0.0602 hCV27474895 rs3756011 hCV3230022rs11132383 0.51 0.046522553 0.1964 hCV27474895 rs3756011 hCV3230025rs3756009 0.51 0.046522553 0.8008 hCV27474895 rs3756011 hCV3230030rs4253408 0.51 0.046522553 0.0889 hCV27474895 rs3756011 hCV3230031rs4253419 0.51 0.046522553 0.1355 hCV27474895 rs3756011 hCV3230032rs5974 0.51 0.046522553 0.0964 hCV27474895 rs3756011 hCV3230038rs2289252 0.51 0.046522553 1 hCV27474895 rs3756011 hCV3230083 rs100136530.51 0.046522553 0.2455 hCV27474895 rs3756011 hCV3230084 rs7682918 0.510.046522553 0.1899 hCV27474895 rs3756011 hCV3230094 rs7687818 0.510.046522553 0.2475 hCV27474895 rs3756011 hCV3230096 rs3817184 0.510.046522553 0.1852 hCV27474895 rs3756011 hCV3230097 rs3736455 0.510.046522553 0.181 hCV27474895 rs3756011 hCV3230113 rs1053094 0.510.046522553 0.1126 hCV27474895 rs3756011 hCV3230118 rs4253429 0.510.046522553 0.1355 hCV27474895 rs3756011 hCV3230119 rs4253430 0.510.046522553 0.3739 hCV27474895 rs3756011 hCV3230121 rs4253431 0.510.046522553 0.0964 hCV27474895 rs3756011 hCV3230125 rs11938564 0.510.046522553 0.198 hCV27474895 rs3756011 hCV3230131 rs13136269 0.510.046522553 0.2952 hCV27474895 rs3756011 hCV3230133 rs12511874 0.510.046522553 0.2952 hCV27474895 rs3756011 hCV3230134 rs12500151 0.510.046522553 0.2952 hCV27474895 rs3756011 hCV3230136 rs13116273 0.510.046522553 0.2675 hCV27474895 rs3756011 hCV32313006 rs4253248 0.510.046522553 0.1192 hCV27474895 rs3756011 hCV32313007 rs4862666 0.510.046522553 0.0748 hCV27474895 rs3756011 hCV32313014 rs4253243 0.510.046522553 0.0475 hCV27474895 rs3756011 hCV32358975 rs4253255 0.510.046522553 0.0845 hCV27474895 rs3756011 hCV8241628 rs907439 0.510.046522553 0.1096 hCV27474895 rs3756011 hCV8241630 rs925451 0.510.046522553 0.7876 hCV27474895 rs3756011 hCV8241631 rs1511802 0.510.046522553 0.2015 hCV27474895 rs3756011 hCV8241632 rs1511801 0.510.046522553 0.083 hCV27474895 rs3756011 hCV8241633 rs1511800 0.510.046522553 0.0748 hCV27474895 rs3756011 hCV8241668 rs1401570 0.510.046522553 0.0565 hCV27474895 rs3756011 hDV68550952 rs4253289 0.510.046522553 0.0624 hCV27474895 rs3756011 hDV71222711 rs4253252 0.510.046522553 0.1192 hCV27474984 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hCV12066124 rs2036914 0.510.052089996 0.5443 hCV27477533 rs3756008 hCV12066129 rs1593 0.510.052089996 0.0893 hCV27477533 rs3756008 hCV1333090 rs6816112 0.510.052089996 0.0736 hCV27477533 rs3756008 hCV1333099 rs10020635 0.510.052089996 0.0654 hCV27477533 rs3756008 hCV15793897 rs3087505 0.510.052089996 0.0633 hCV27477533 rs3756008 hCV15811716 rs2102575 0.510.052089996 0.0597 hCV27477533 rs3756008 hCV15968025 rs2292425 0.510.052089996 0.156 hCV27477533 rs3756008 hCV15968026 rs2292426 0.510.052089996 0.2168 hCV27477533 rs3756008 hCV15968034 rs2292428 0.510.052089996 0.1109 hCV27477533 rs3756008 hCV15968043 rs2292423 0.510.052089996 0.3624 hCV27477533 rs3756008 hCV16172925 rs2241818 0.510.052089996 0.0782 hCV27477533 rs3756008 hCV16172935 rs2241817 0.510.052089996 0.2699 hCV27477533 rs3756008 hCV2103343 rs4241824 0.510.052089996 0.5858 hCV27477533 rs3756008 hCV2103348 rs11931515 0.510.052089996 0.0563 hCV27477533 rs3756008 hCV2103388 rs4613610 0.510.052089996 0.0953 hCV27477533 rs3756008 hCV2103391 rs1008728 0.510.052089996 0.1778 hCV27477533 rs3756008 hCV2103392 rs12500826 0.510.052089996 0.3498 hCV27477533 rs3756008 hCV22272267 rs3733402 0.510.052089996 0.1577 hCV27477533 rs3756008 hCV25474413 rs3822057 0.510.052089996 0.577 hCV27477533 rs3756008 hCV25474414 rs4253399 0.510.052089996 0.9414 hCV27477533 rs3756008 hCV25634754 rs4253331 0.510.052089996 0.1183 hCV27477533 rs3756008 hCV25988221 rs9995366 0.510.052089996 0.067 hCV27477533 rs3756008 hCV25990131 rs13146272 0.510.052089996 0.1634 hCV27477533 rs3756008 hCV26038139 rs4253405 0.510.052089996 0.3634 hCV27477533 rs3756008 hCV26265231 rs7684025 0.510.052089996 0.2597 hCV27477533 rs3756008 hCV27309972 rs13101296 0.510.052089996 0.1249 hCV27477533 rs3756008 hCV27309991 rs4572916 0.510.052089996 0.1028 hCV27477533 rs3756008 hCV27473099 rs3733403 0.510.052089996 0.081 hCV27477533 rs3756008 hCV27474895 rs3756011 0.510.052089996 0.7565 hCV27477533 rs3756008 hCV27490984 rs3822058 0.510.052089996 0.2804 hCV27477533 rs3756008 hCV27521729 rs3822056 0.510.052089996 0.0979 hCV27477533 rs3756008 hCV27902803 rs4862665 0.510.052089996 0.067 hCV27477533 rs3756008 hCV27902808 rs4253236 0.510.052089996 0.0524 hCV27477533 rs3756008 hCV28960679 rs6844764 0.510.052089996 0.1972 hCV27477533 rs3756008 hCV29053261 rs6842047 0.510.052089996 0.0633 hCV27477533 rs3756008 hCV29053264 rs7667777 0.510.052089996 0.2846 hCV27477533 rs3756008 hCV29053265 rs4253244 0.510.052089996 0.0589 hCV27477533 rs3756008 hCV29718000 rs4253238 0.510.052089996 0.1722 hCV27477533 rs3756008 hCV29826351 rs10025990 0.510.052089996 0.0992 hCV27477533 rs3756008 hCV29877725 rs4253295 0.510.052089996 0.248 hCV27477533 rs3756008 hCV30492573 rs10471184 0.510.052089996 0.0633 hCV27477533 rs3756008 hCV30983902 rs4862668 0.510.052089996 0.0836 hCV27477533 rs3756008 hCV30983927 rs6552962 0.510.052089996 0.0937 hCV27477533 rs3756008 hCV32209629 rs12715865 0.510.052089996 0.1094 hCV27477533 rs3756008 hCV32209636 rs11132387 0.510.052089996 0.3591 hCV27477533 rs3756008 hCV32209637 rs13143773 0.510.052089996 0.1889 hCV27477533 rs3756008 hCV32209638 rs12507040 0.510.052089996 0.19 hCV27477533 rs3756008 hCV32291256 rs4253406 0.510.052089996 0.1099 hCV27477533 rs3756008 hCV32291269 rs4253417 0.510.052089996 0.7459 hCV27477533 rs3756008 hCV32291286 rs4253422 0.510.052089996 0.145 hCV27477533 rs3756008 hCV32291287 rs4253423 0.510.052089996 0.145 hCV27477533 rs3756008 hCV32291295 rs4253292 0.510.052089996 0.0659 hCV27477533 rs3756008 hCV3229991 rs4241815 0.510.052089996 0.1577 hCV27477533 rs3756008 hCV3229992 rs3775298 0.510.052089996 0.1577 hCV27477533 rs3756008 hCV3229995 rs11132382 0.510.052089996 0.1702 hCV27477533 rs3756008 hCV3230000 rs4253294 0.510.052089996 0.0691 hCV27477533 rs3756008 hCV3230002 rs4253297 0.510.052089996 0.3082 hCV27477533 rs3756008 hCV3230003 rs2304595 0.510.052089996 0.3373 hCV27477533 rs3756008 hCV3230004 rs4253301 0.510.052089996 0.0562 hCV27477533 rs3756008 hCV3230006 rs4253308 0.510.052089996 0.248 hCV27477533 rs3756008 hCV3230007 rs4253311 0.510.052089996 0.1577 hCV27477533 rs3756008 hCV3230010 rs4253315 0.510.052089996 0.0836 hCV27477533 rs3756008 hCV3230011 rs4253320 0.510.052089996 0.3082 hCV27477533 rs3756008 hCV3230013 rs3775303 0.510.052089996 0.3791 hCV27477533 rs3756008 hCV3230014 rs4861709 0.510.052089996 0.0691 hCV27477533 rs3756008 hCV3230016 rs4253325 0.510.052089996 0.0821 hCV27477533 rs3756008 hCV3230017 rs4253327 0.510.052089996 0.117 hCV27477533 rs3756008 hCV3230018 rs925453 0.510.052089996 0.0596 hCV27477533 rs3756008 hCV3230019 rs4253332 0.510.052089996 0.0555 hCV27477533 rs3756008 hCV3230021 rs13135645 0.510.052089996 0.0833 hCV27477533 rs3756008 hCV3230022 rs11132383 0.510.052089996 0.3776 hCV27477533 rs3756008 hCV3230025 rs3756009 0.510.052089996 1 hCV27477533 rs3756008 hCV3230030 rs4253408 0.510.052089996 0.1104 hCV27477533 rs3756008 hCV3230031 rs4253419 0.510.052089996 0.145 hCV27477533 rs3756008 hCV3230038 rs2289252 0.510.052089996 0.7249 hCV27477533 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rs1538773 0.51 0.430712711 0.7354 hCV31523650 rs12048930hDV69368808 rs12145558 0.51 0.430712711 0.5119 hCV31523650 rs12048930hDV71836703 rs6429433 0.51 0.430712711 0.7322 hCV31523650 rs12048930hDV90784784 rs320339 0.51 0.430712711 0.9053 hCV32291301 rs4253302hCV15968025 rs2292425 0.51 0.239176625 0.382 hCV32291301 rs4253302hCV15968026 rs2292426 0.51 0.239176625 0.4222 hCV32291301 rs4253302hCV15968034 rs2292428 0.51 0.239176625 0.3408 hCV32291301 rs4253302hCV15975109 rs2304596 0.51 0.239176625 1 hCV32291301 rs4253302hCV22272267 rs3733402 0.51 0.239176625 0.2397 hCV32291301 rs4253302hCV25989001 hCV25989001 0.51 0.239176625 0.9447 hCV32291301 rs4253302hCV25990131 rs13146272 0.51 0.239176625 0.3944 hCV32291301 rs4253302hCV27482765 rs3775301 0.51 0.239176625 1 hCV32291301 rs4253302hCV27902808 rs4253236 0.51 0.239176625 0.3677 hCV32291301 rs4253302hCV28960679 rs6844764 0.51 0.239176625 0.2663 hCV32291301 rs4253302hCV29053265 rs4253244 0.51 0.239176625 0.3178 hCV32291301 rs4253302hCV29718000 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rs2289252hCV3230006 rs4253308 0.51 0.044201827 0.1339 hCV3230038 rs2289252hCV3230007 rs4253311 0.51 0.044201827 0.1192 hCV3230038 rs2289252hCV3230010 rs4253315 0.51 0.044201827 0.0748 hCV3230038 rs2289252hCV3230011 rs4253320 0.51 0.044201827 0.2015 hCV3230038 rs2289252hCV3230013 rs3775303 0.51 0.044201827 0.2636 hCV3230038 rs2289252hCV3230016 rs4253325 0.51 0.044201827 0.0662 hCV3230038 rs2289252hCV3230017 rs4253327 0.51 0.044201827 0.0771 hCV3230038 rs2289252hCV3230021 rs13135645 0.51 0.044201827 0.0564 hCV3230038 rs2289252hCV3230022 rs11132383 0.51 0.044201827 0.2455 hCV3230038 rs2289252hCV3230025 rs3756009 0.51 0.044201827 0.7937 hCV3230038 rs2289252hCV3230030 rs4253408 0.51 0.044201827 0.0719 hCV3230038 rs2289252hCV3230031 rs4253419 0.51 0.044201827 0.1539 hCV3230038 rs2289252hCV3230032 rs5974 0.51 0.044201827 0.1125 hCV3230038 rs2289252hCV3230083 rs10013653 0.51 0.044201827 0.2181 hCV3230038 rs2289252hCV3230084 rs7682918 0.51 0.044201827 0.1434 hCV3230038 rs2289252hCV3230094 rs7687818 0.51 0.044201827 0.2201 hCV3230038 rs2289252hCV3230096 rs3817184 0.51 0.044201827 0.1484 hCV3230038 rs2289252hCV3230097 rs3736455 0.51 0.044201827 0.1419 hCV3230038 rs2289252hCV3230101 rs6835839 0.51 0.044201827 0.0447 hCV3230038 rs2289252hCV3230106 rs1473597 0.51 0.044201827 0.0873 hCV3230038 rs2289252hCV3230110 rs2276917 0.51 0.044201827 0.0803 hCV3230038 rs2289252hCV3230113 rs1053094 0.51 0.044201827 0.1432 hCV3230038 rs2289252hCV3230118 rs4253429 0.51 0.044201827 0.1539 hCV3230038 rs2289252hCV3230119 rs4253430 0.51 0.044201827 0.3973 hCV3230038 rs2289252hCV3230121 rs4253431 0.51 0.044201827 0.0887 hCV3230038 rs2289252hCV3230125 rs11938564 0.51 0.044201827 0.2052 hCV3230038 rs2289252hCV3230131 rs13136269 0.51 0.044201827 0.2973 hCV3230038 rs2289252hCV3230133 rs12511874 0.51 0.044201827 0.2104 hCV3230038 rs2289252hCV3230134 rs12500151 0.51 0.044201827 0.3043 hCV3230038 rs2289252hCV3230136 rs13116273 0.51 0.044201827 0.2952 hCV3230038 rs2289252hCV32313006 rs4253248 0.51 0.044201827 0.1068 hCV3230038 rs2289252hCV32313007 rs4862666 0.51 0.044201827 0.0512 hCV3230038 rs2289252hCV32313014 rs4253243 0.51 0.044201827 0.0636 hCV3230038 rs2289252hCV32358975 rs4253255 0.51 0.044201827 0.1152 hCV3230038 rs2289252hCV32358984 rs4253256 0.51 0.044201827 0.0489 hCV3230038 rs2289252hCV8241628 rs907439 0.51 0.044201827 0.1232 hCV3230038 rs2289252hCV8241630 rs925451 0.51 0.044201827 0.7423 hCV3230038 rs2289252hCV8241631 rs1511802 0.51 0.044201827 0.1452 hCV3230038 rs2289252hCV8241632 rs1511801 0.51 0.044201827 0.1183 hCV3230038 rs2289252hCV8241633 rs1511800 0.51 0.044201827 0.0512 hCV3230038 rs2289252hDV68550952 rs4253289 0.51 0.044201827 0.0632 hCV3230038 rs2289252hDV71222711 rs4253252 0.51 0.044201827 0.1068 hCV3230096 rs3817184hCV11786147 rs4862662 0.51 0.10562155 0.9607 hCV3230096 rs3817184hCV11786235 rs4253287 0.51 0.10562155 0.1611 hCV3230096 rs3817184hCV11786258 rs4253303 0.51 0.10562155 0.7346 hCV3230096 rs3817184hCV11786259 rs4253304 0.51 0.10562155 0.6556 hCV3230096 rs3817184hCV12066106 rs1914926 0.51 0.10562155 0.1148 hCV3230096 rs3817184hCV12066118 rs2048 0.51 0.10562155 0.3722 hCV3230096 rs3817184hCV12066119 rs1912826 0.51 0.10562155 0.3754 hCV3230096 rs3817184hCV12066124 rs2036914 0.51 0.10562155 0.2824 hCV3230096 rs3817184hCV15968025 rs2292425 0.51 0.10562155 0.414 hCV3230096 rs3817184hCV15968026 rs2292426 0.51 0.10562155 0.3737 hCV3230096 rs3817184hCV15968034 rs2292428 0.51 0.10562155 0.4839 hCV3230096 rs3817184hCV15968043 rs2292423 0.51 0.10562155 0.6453 hCV3230096 rs3817184hCV15975109 rs2304596 0.51 0.10562155 0.1582 hCV3230096 rs3817184hCV2103343 rs4241824 0.51 0.10562155 0.2431 hCV3230096 rs3817184hCV22272267 rs3733402 0.51 0.10562155 0.3722 hCV3230096 rs3817184hCV25474413 rs3822057 0.51 0.10562155 0.2412 hCV3230096 rs3817184hCV25474414 rs4253399 0.51 0.10562155 0.1977 hCV3230096 rs3817184hCV25989001 hCV25989001 0.51 0.10562155 0.1672 hCV3230096 rs3817184hCV25990131 rs13146272 0.51 0.10562155 0.4248 hCV3230096 rs3817184hCV26038139 rs4253405 0.51 0.10562155 0.1427 hCV3230096 rs3817184hCV26265231 rs7684025 0.51 0.10562155 0.7723 hCV3230096 rs3817184hCV27474895 rs3756011 0.51 0.10562155 0.1852 hCV3230096 rs3817184hCV27477533 rs3756008 0.51 0.10562155 0.2279 hCV3230096 rs3817184hCV27482765 rs3775301 0.51 0.10562155 0.1582 hCV3230096 rs3817184hCV27902808 rs4253236 0.51 0.10562155 0.2369 hCV3230096 rs3817184hCV28960679 rs6844764 0.51 0.10562155 0.4298 hCV3230096 rs3817184hCV29053260 rs4861707 0.51 0.10562155 0.2941 hCV3230096 rs3817184hCV29053264 rs7667777 0.51 0.10562155 1 hCV3230096 rs3817184 hCV29053265rs4253244 0.51 0.10562155 0.2244 hCV3230096 rs3817184 hCV29053266rs7687961 0.51 0.10562155 0.1405 hCV3230096 rs3817184 hCV29053271rs6814261 0.51 0.10562155 0.1124 hCV3230096 rs3817184 hCV29718000rs4253238 0.51 0.10562155 0.3705 hCV3230096 rs3817184 hCV29877725rs4253295 0.51 0.10562155 0.7382 hCV3230096 rs3817184 hCV30983927rs6552962 0.51 0.10562155 0.1582 hCV3230096 rs3817184 hCV32209636rs11132387 0.51 0.10562155 0.1797 hCV3230096 rs3817184 hCV32209638rs12507040 0.51 0.10562155 0.1135 hCV3230096 rs3817184 hCV32291217rs4253323 0.51 0.10562155 0.1582 hCV3230096 rs3817184 hCV32291269rs4253417 0.51 0.10562155 0.1798 hCV3230096 rs3817184 hCV32291295rs4253292 0.51 0.10562155 0.1783 hCV3230096 rs3817184 hCV32291301rs4253302 0.51 0.10562155 0.1573 hCV3230096 rs3817184 hCV32295028rs4253260 0.51 0.10562155 0.1582 hCV3230096 rs3817184 hCV3229991rs4241815 0.51 0.10562155 0.3722 hCV3230096 rs3817184 hCV3229992rs3775298 0.51 0.10562155 0.3722 hCV3230096 rs3817184 hCV3229995rs11132382 0.51 0.10562155 0.3745 hCV3230096 rs3817184 hCV3230000rs4253294 0.51 0.10562155 0.1467 hCV3230096 rs3817184 hCV3230002rs4253297 0.51 0.10562155 0.7524 hCV3230096 rs3817184 hCV3230003rs2304595 0.51 0.10562155 0.6237 hCV3230096 rs3817184 hCV3230006rs4253308 0.51 0.10562155 0.7382 hCV3230096 rs3817184 hCV3230007rs4253311 0.51 0.10562155 0.3722 hCV3230096 rs3817184 hCV3230011rs4253320 0.51 0.10562155 0.7524 hCV3230096 rs3817184 hCV3230013rs3775303 0.51 0.10562155 0.6556 hCV3230096 rs3817184 hCV3230014rs4861709 0.51 0.10562155 0.1467 hCV3230096 rs3817184 hCV3230017rs4253327 0.51 0.10562155 0.207 hCV3230096 rs3817184 hCV3230018 rs9254530.51 0.10562155 0.1144 hCV3230096 rs3817184 hCV3230019 rs4253332 0.510.10562155 0.1092 hCV3230096 rs3817184 hCV3230022 rs11132383 0.510.10562155 0.2117 hCV3230096 rs3817184 hCV3230025 rs3756009 0.510.10562155 0.2784 hCV3230096 rs3817184 hCV3230038 rs2289252 0.510.10562155 0.1484 hCV3230096 rs3817184 hCV3230079 rs35641294 0.510.10562155 0.1147 hCV3230096 rs3817184 hCV3230083 rs10013653 0.510.10562155 0.7047 hCV3230096 rs3817184 hCV3230084 rs7682918 0.510.10562155 0.8657 hCV3230096 rs3817184 hCV3230094 rs7687818 0.510.10562155 0.8722 hCV3230096 rs3817184 hCV3230097 rs3736455 0.510.10562155 0.367 hCV3230096 rs3817184 hCV3230101 rs6835839 0.510.10562155 0.451 hCV3230096 rs3817184 hCV3230106 rs1473597 0.510.10562155 0.4966 hCV3230096 rs3817184 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hCV3230113 rs1053094 hCV27310218 rs9992614 0.510.086445499 0.0932 hCV3230113 rs1053094 hCV27310253 rs13108688 0.510.086445499 0.1242 hCV3230113 rs1053094 hCV27310255 rs7657186 0.510.086445499 0.1279 hCV3230113 rs1053094 hCV27474895 rs3756011 0.510.086445499 0.1126 hCV3230113 rs1053094 hCV27477533 rs3756008 0.510.086445499 0.2208 hCV3230113 rs1053094 hCV27482765 rs3775301 0.510.086445499 0.2245 hCV3230113 rs1053094 hCV27490984 rs3822058 0.510.086445499 0.096 hCV3230113 rs1053094 hCV27506149 rs3822055 0.510.086445499 0.1041 hCV3230113 rs1053094 hCV27902803 rs4862665 0.510.086445499 0.1117 hCV3230113 rs1053094 hCV27902808 rs4253236 0.510.086445499 0.3483 hCV3230113 rs1053094 hCV28960679 rs6844764 0.510.086445499 0.1995 hCV3230113 rs1053094 hCV29053260 rs4861707 0.510.086445499 0.0954 hCV3230113 rs1053094 hCV29053261 rs6842047 0.510.086445499 0.1117 hCV3230113 rs1053094 hCV29053264 rs7667777 0.510.086445499 0.6901 hCV3230113 rs1053094 hCV29053265 rs4253244 0.510.086445499 0.3493 hCV3230113 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0.510.086445499 0.2344 hCV3230113 rs1053094 hCV3230101 rs6835839 0.510.086445499 0.6667 hCV3230113 rs1053094 hCV3230106 rs1473597 0.510.086445499 0.6384 hCV3230113 rs1053094 hCV3230110 rs2276917 0.510.086445499 0.6489 hCV3230113 rs1053094 hCV3230118 rs4253429 0.510.086445499 0.2024 hCV3230113 rs1053094 hCV3230119 rs4253430 0.510.086445499 0.096 hCV3230113 rs1053094 hCV3230125 rs11938564 0.510.086445499 0.1519 hCV3230113 rs1053094 hCV3230131 rs13136269 0.510.086445499 0.0986 hCV3230113 rs1053094 hCV3230133 rs12511874 0.510.086445499 0.0986 hCV3230113 rs1053094 hCV3230134 rs12500151 0.510.086445499 0.0986 hCV3230113 rs1053094 hCV3230136 rs13116273 0.510.086445499 0.1269 hCV3230113 rs1053094 hCV32313006 rs4253248 0.510.086445499 0.552 hCV3230113 rs1053094 hCV32313007 rs4862666 0.510.086445499 0.1117 hCV3230113 rs1053094 hCV32313024 rs4253239 0.510.086445499 0.2276 hCV3230113 rs1053094 hCV32358975 rs4253255 0.510.086445499 0.573 hCV3230113 rs1053094 hCV32358984 rs4253256 0.510.086445499 0.3678 hCV3230113 rs1053094 hCV441385 rs1983369 0.510.086445499 0.1249 hCV3230113 rs1053094 hCV79084 rs1519312 0.510.086445499 0.1129 hCV3230113 rs1053094 hCV8241630 rs925451 0.510.086445499 0.207 hCV3230113 rs1053094 hCV8241631 rs1511802 0.510.086445499 0.5019 hCV3230113 rs1053094 hCV8241632 rs1511801 0.510.086445499 0.6225 hCV3230113 rs1053094 hCV8241633 rs1511800 0.510.086445499 0.1117 hCV3230113 rs1053094 hCV8241661 rs1715051 0.510.086445499 0.1249 hCV3230113 rs1053094 hDV71222711 rs4253252 0.510.086445499 0.552 hCV3230113 rs1053094 hDV76175111 rs35079309 0.510.086445499 0.2766 hCV596331 rs6048 hCV2288124 rs440051 0.51 0.2564321060.4103 hCV596331 rs6048 hCV26016183 rs9887617 0.51 0.256432106 0.3131hCV596331 rs6048 hCV26225376 rs3117074 0.51 0.256432106 0.4074 hCV596331rs6048 hCV26225377 rs12008759 0.51 0.256432106 0.4103 hCV596331 rs6048hCV2969899 rs434144 0.51 0.256432106 0.3772 hCV596331 rs6048 hCV2969900rs434447 0.51 0.256432106 0.4074 hCV596331 rs6048 hCV2986569 rs110958010.51 0.256432106 0.4074 hCV596331 rs6048 hCV2986570 rs3117458 0.510.256432106 0.3714 hCV596331 rs6048 hCV2986572 rs4149670 0.510.256432106 0.4393 hCV596331 rs6048 hCV2986574 rs4149672 0.510.256432106 0.602 hCV596331 rs6048 hCV2986575 rs4149674 0.51 0.2564321060.602 hCV596331 rs6048 hCV596323 rs438601 0.51 0.256432106 0.5056hCV596331 rs6048 hCV596326 rs398101 0.51 0.256432106 0.8045 hCV596331rs6048 hCV596330 rs422187 0.51 0.256432106 0.9745 hCV596331 rs6048hCV596335 rs413957 0.51 0.256432106 0.4074 hCV596331 rs6048 hCV596336rs110583 0.51 0.256432106 0.4329 hCV596331 rs6048 hCV596337 rs4217660.51 0.256432106 0.4329 hCV596331 rs6048 hCV596339 rs370713 0.510.256432106 0.4103 hCV596331 rs6048 hCV596340 rs413536 0.51 0.2564321060.3724 hCV596331 rs6048 hCV596344 rs445691 0.51 0.256432106 0.4103hCV596331 rs6048 hCV596669 rs376165 0.51 0.256432106 0.6589 hCV596331rs6048 hDV70794854 rs17002122 0.51 0.256432106 0.3457 hCV596331 rs6048hDV71066592 rs17002116 0.51 0.256432106 0.2766 hCV596331 rs6048hDV76976791 rs4149758 0.51 0.256432106 0.3068 hCV8241630 rs925451hCV11786147 rs4862662 0.51 0.047967528 0.1977 hCV8241630 rs925451hCV11786235 rs4253287 0.51 0.047967528 0.0779 hCV8241630 rs925451hCV11786258 rs4253303 0.51 0.047967528 0.2889 hCV8241630 rs925451hCV11786259 rs4253304 0.51 0.047967528 0.3548 hCV8241630 rs925451hCV11786295 rs4253421 0.51 0.047967528 0.0512 hCV8241630 rs925451hCV11786307 rs1062547 0.51 0.047967528 0.3046 hCV8241630 rs925451hCV11786327 rs13133050 0.51 0.047967528 0.1424 hCV8241630 rs925451hCV12066116 rs1877320 0.51 0.047967528 0.0806 hCV8241630 rs925451hCV12066118 rs2048 0.51 0.047967528 0.1423 hCV8241630 rs925451hCV12066119 rs1912826 0.51 0.047967528 0.1513 hCV8241630 rs925451hCV12066124 rs2036914 0.51 0.047967528 0.5632 hCV8241630 rs925451hCV12066129 rs1593 0.51 0.047967528 0.0859 hCV8241630 rs925451hCV1333083 rs10022988 0.51 0.047967528 0.0533 hCV8241630 rs925451hCV1333090 rs6816112 0.51 0.047967528 0.0839 hCV8241630 rs925451hCV1333097 rs4862680 0.51 0.047967528 0.0533 hCV8241630 rs925451hCV1333099 rs10020635 0.51 0.047967528 0.0737 hCV8241630 rs925451hCV15793897 rs3087505 0.51 0.047967528 0.0621 hCV8241630 rs925451hCV15811716 rs2102575 0.51 0.047967528 0.0585 hCV8241630 rs925451hCV15968025 rs2292425 0.51 0.047967528 0.1498 hCV8241630 rs925451hCV15968026 rs2292426 0.51 0.047967528 0.2045 hCV8241630 rs925451hCV15968034 rs2292428 0.51 0.047967528 0.1077 hCV8241630 rs925451hCV15968043 rs2292423 0.51 0.047967528 0.338 hCV8241630 rs925451hCV16172925 rs2241818 0.51 0.047967528 0.0837 hCV8241630 rs925451hCV16172935 rs2241817 0.51 0.047967528 0.287 hCV8241630 rs925451hCV2103343 rs4241824 0.51 0.047967528 0.605 hCV8241630 rs925451hCV2103348 rs11931515 0.51 0.047967528 0.0499 hCV8241630 rs925451hCV2103388 rs4613610 0.51 0.047967528 0.0893 hCV8241630 rs925451hCV2103391 rs1008728 0.51 0.047967528 0.1739 hCV8241630 rs925451hCV2103392 rs12500826 0.51 0.047967528 0.3352 hCV8241630 rs925451hCV22272267 rs3733402 0.51 0.047967528 0.1476 hCV8241630 rs925451hCV25474413 rs3822057 0.51 0.047967528 0.596 hCV8241630 rs925451hCV25474414 rs4253399 0.51 0.047967528 0.9606 hCV8241630 rs925451hCV25634754 rs4253331 0.51 0.047967528 0.0907 hCV8241630 rs925451hCV25988221 rs9995366 0.51 0.047967528 0.0657 hCV8241630 rs925451hCV25990131 rs13146272 0.51 0.047967528 0.1564 hCV8241630 rs925451hCV26038139 rs4253405 0.51 0.047967528 0.3823 hCV8241630 rs925451hCV26265231 rs7684025 0.51 0.047967528 0.2509 hCV8241630 rs925451hCV27309972 rs13101296 0.51 0.047967528 0.1189 hCV8241630 rs925451hCV27309991 rs4572916 0.51 0.047967528 0.0972 hCV8241630 rs925451hCV27473099 rs3733403 0.51 0.047967528 0.078 hCV8241630 rs925451hCV27474895 rs3756011 0.51 0.047967528 0.7876 hCV8241630 rs925451hCV27477533 rs3756008 0.51 0.047967528 0.9804 hCV8241630 rs925451hCV27490984 rs3822058 0.51 0.047967528 0.2976 hCV8241630 rs925451hCV27521729 rs3822056 0.51 0.047967528 0.096 hCV8241630 rs925451hCV27902803 rs4862665 0.51 0.047967528 0.0657 hCV8241630 rs925451hCV27902808 rs4253236 0.51 0.047967528 0.0514 hCV8241630 rs925451hCV28960679 rs6844764 0.51 0.047967528 0.1817 hCV8241630 rs925451hCV29053261 rs6842047 0.51 0.047967528 0.0621 hCV8241630 rs925451hCV29053264 rs7667777 0.51 0.047967528 0.2641 hCV8241630 rs925451hCV29053265 rs4253244 0.51 0.047967528 0.0566 hCV8241630 rs925451hCV29718000 rs4253238 0.51 0.047967528 0.1666 hCV8241630 rs925451hCV29826351 rs10025990 0.51 0.047967528 0.0954 hCV8241630 rs925451hCV29877725 rs4253295 0.51 0.047967528 0.2376 hCV8241630 rs925451hCV30492573 rs10471184 0.51 0.047967528 0.0621 hCV8241630 rs925451hCV30983902 rs4862668 0.51 0.047967528 0.0806 hCV8241630 rs925451hCV30983927 rs6552962 0.51 0.047967528 0.0884 hCV8241630 rs925451hCV32209629 rs12715865 0.51 0.047967528 0.1026 hCV8241630 rs925451hCV32209636 rs11132387 0.51 0.047967528 0.3826 hCV8241630 rs925451hCV32209637 rs13143773 0.51 0.047967528 0.2155 hCV8241630 rs925451hCV32209638 rs12507040 0.51 0.047967528 0.2055 hCV8241630 rs925451hCV32291256 rs4253406 0.51 0.047967528 0.1121 hCV8241630 rs925451hCV32291269 rs4253417 0.51 0.047967528 0.7639 hCV8241630 rs925451hCV32291286 rs4253422 0.51 0.047967528 0.1422 hCV8241630 rs925451hCV32291287 rs4253423 0.51 0.047967528 0.1422 hCV8241630 rs925451hCV32291295 rs4253292 0.51 0.047967528 0.0633 hCV8241630 rs925451hCV3229991 rs4241815 0.51 0.047967528 0.1476 hCV8241630 rs925451hCV3229992 rs3775298 0.51 0.047967528 0.1476 hCV8241630 rs925451hCV3229995 rs11132382 0.51 0.047967528 0.1645 hCV8241630 rs925451hCV3230000 rs4253294 0.51 0.047967528 0.0677 hCV8241630 rs925451hCV3230002 rs4253297 0.51 0.047967528 0.2853 hCV8241630 rs925451hCV3230003 rs2304595 0.51 0.047967528 0.3258 hCV8241630 rs925451hCV3230004 rs4253301 0.51 0.047967528 0.0548 hCV8241630 rs925451hCV3230006 rs4253308 0.51 0.047967528 0.2376 hCV8241630 rs925451hCV3230007 rs4253311 0.51 0.047967528 0.1476 hCV8241630 rs925451hCV3230010 rs4253315 0.51 0.047967528 0.0806 hCV8241630 rs925451hCV3230011 rs4253320 0.51 0.047967528 0.2853 hCV8241630 rs925451hCV3230013 rs3775303 0.51 0.047967528 0.3548 hCV8241630 rs925451hCV3230014 rs4861709 0.51 0.047967528 0.0677 hCV8241630 rs925451hCV3230016 rs4253325 0.51 0.047967528 0.0805 hCV8241630 rs925451hCV3230017 rs4253327 0.51 0.047967528 0.1125 hCV8241630 rs925451hCV3230018 rs925453 0.51 0.047967528 0.0593 hCV8241630 rs925451hCV3230019 rs4253332 0.51 0.047967528 0.0554 hCV8241630 rs925451hCV3230021 rs13135645 0.51 0.047967528 0.0814 hCV8241630 rs925451hCV3230022 rs11132383 0.51 0.047967528 0.3677 hCV8241630 rs925451hCV3230025 rs3756009 0.51 0.047967528 1 hCV8241630 rs925451 hCV3230030rs4253408 0.51 0.047967528 0.1145 hCV8241630 rs925451 hCV3230031rs4253419 0.51 0.047967528 0.1422 hCV8241630 rs925451 hCV3230038rs2289252 0.51 0.047967528 0.7423 hCV8241630 rs925451 hCV3230051rs4862658 0.51 0.047967528 0.0538 hCV8241630 rs925451 hCV3230083rs10013653 0.51 0.047967528 0.2951 hCV8241630 rs925451 hCV3230084rs7682918 0.51 0.047967528 0.2117 hCV8241630 rs925451 hCV3230094rs7687818 0.51 0.047967528 0.3063 hCV8241630 rs925451 hCV3230096rs3817184 0.51 0.047967528 0.2184 hCV8241630 rs925451 hCV3230097rs3736455 0.51 0.047967528 0.2161 hCV8241630 rs925451 hCV3230101rs6835839 0.51 0.047967528 0.0876 hCV8241630 rs925451 hCV3230106rs1473597 0.51 0.047967528 0.127 hCV8241630 rs925451 hCV3230110rs2276917 0.51 0.047967528 0.1184 hCV8241630 rs925451 hCV3230113rs1053094 0.51 0.047967528 0.207 hCV8241630 rs925451 hCV3230118rs4253429 0.51 0.047967528 0.1422 hCV8241630 rs925451 hCV3230119rs4253430 0.51 0.047967528 0.2905 hCV8241630 rs925451 hCV3230125rs11938564 0.51 0.047967528 0.1896 hCV8241630 rs925451 hCV3230131rs13136269 0.51 0.047967528 0.2055 hCV8241630 rs925451 hCV3230133rs12511874 0.51 0.047967528 0.1512 hCV8241630 rs925451 hCV3230134rs12500151 0.51 0.047967528 0.2115 hCV8241630 rs925451 hCV3230136rs13116273 0.51 0.047967528 0.229 hCV8241630 rs925451 hCV32313006rs4253248 0.51 0.047967528 0.1736 hCV8241630 rs925451 hCV32313007rs4862666 0.51 0.047967528 0.0657 hCV8241630 rs925451 hCV32313014rs4253243 0.51 0.047967528 0.0907 hCV8241630 rs925451 hCV32313024rs4253239 0.51 0.047967528 0.0633 hCV8241630 rs925451 hCV32358975rs4253255 0.51 0.047967528 0.1454 hCV8241630 rs925451 hCV32358984rs4253256 0.51 0.047967528 0.0647 hCV8241630 rs925451 hCV8241628rs907439 0.51 0.047967528 0.0972 hCV8241630 rs925451 hCV8241631rs1511802 0.51 0.047967528 0.2539 hCV8241630 rs925451 hCV8241632rs1511801 0.51 0.047967528 0.1877 hCV8241630 rs925451 hCV8241633rs1511800 0.51 0.047967528 0.0657 hCV8241630 rs925451 hDV68550952rs4253289 0.51 0.047967528 0.0659 hCV8241630 rs925451 hDV71222711rs4253252 0.51 0.047967528 0.1736 hCV8717873 rs1613662 hCV11977629rs1654459 0.51 0.291390182 0.824 hCV8717873 rs1613662 hCV1376257rs10416380 0.51 0.291390182 0.688 hCV8717873 rs1613662 hCV1376262rs1671150 0.51 0.291390182 0.7101 hCV8717873 rs1613662 hCV1376264rs1671151 0.51 0.291390182 0.7101 hCV8717873 rs1613662 hCV1376265rs1671152 0.51 0.291390182 0.881 hCV8717873 rs1613662 hCV1376266rs1654413 0.51 0.291390182 0.8292 hCV8717873 rs1613662 hCV1376342rs1654416 0.51 0.291390182 0.7313 hCV8717873 rs1613662 hCV1376359rs2886412 0.51 0.291390182 0.8039 hCV8717873 rs1613662 hCV1376386rs1671214 0.51 0.291390182 0.4218 hCV8717873 rs1613662 hCV1376388rs1671215 0.51 0.291390182 0.4218 hCV8717873 rs1613662 hCV1376414rs1671171 0.51 0.291390182 0.4652 hCV8717873 rs1613662 hCV15973734rs2304167 0.51 0.291390182 0.7101 hCV8717873 rs1613662 hCV16044361rs2569513 0.51 0.291390182 0.8557 hCV8717873 rs1613662 hCV26895244rs1671153 0.51 0.291390182 0.7101 hCV8717873 rs1613662 hCV26895257rs2886415 0.51 0.291390182 0.8732 hCV8717873 rs1613662 hCV29271569rs1626971 0.51 0.291390182 0.8853 hCV8717873 rs1613662 hCV31722831rs11671922 0.51 0.291390182 0.8358 hCV8717873 rs1613662 hCV31722832rs11084381 0.51 0.291390182 0.8192 hCV8717873 rs1613662 hCV31722834rs11084382 0.51 0.291390182 0.7187 hCV8717873 rs1613662 hCV31722835rs11668169 0.51 0.291390182 0.8188 hCV8717873 rs1613662 hCV31722836rs11672026 0.51 0.291390182 0.8093 hCV8717873 rs1613662 hCV7841075rs1671196 0.51 0.291390182 0.8192 hCV8717873 rs1613662 hCV8703249rs1654444 0.51 0.291390182 0.8822 hCV8717873 rs1613662 hCV8704962rs775893 0.51 0.291390182 0.5398 hCV8717873 rs1613662 hCV8717751rs1671218 0.51 0.291390182 0.4141 hCV8717873 rs1613662 hCV8717752rs1671217 0.51 0.291390182 0.8853 hCV8717873 rs1613662 hCV8717761rs1654439 0.51 0.291390182 0.776 hCV8717873 rs1613662 hCV8717793rs1654433 0.51 0.291390182 0.8557 hCV8717873 rs1613662 hCV8717794rs1654432 0.51 0.291390182 0.8557 hCV8717873 rs1613662 hCV8717845rs892090 0.51 0.291390182 1 hCV8717873 rs1613662 hCV8717846 rs8920890.51 0.291390182 0.8358 hCV8717873 rs1613662 hCV8717871 rs1654421 0.510.291390182 0.6875 hCV8717873 rs1613662 hCV8717881 rs1654420 0.510.291390182 0.8188 hCV8717873 rs1613662 hCV8717893 rs1671192 0.510.291390182 0.8737 hCV8717873 rs1613662 hCV8718961 rs1654451 0.510.291390182 0.8233 hCV8717873 rs1613662 hCV8718968 rs1671176 0.510.291390182 0.4332 hCV8717873 rs1613662 hCV8718972 rs1654447 0.510.291390182 0.8825 hCV8717873 rs1613662 hCV9490926 rs1654419 0.510.291390182 0.8188 hCV8717873 rs1613662 hDV91225183 rs1671171 0.510.291390182 0.4652 hCV8718961 rs1654451 hCV11977629 rs1654459 0.510.573058702 1 hCV8718961 rs1654451 hCV1376265 rs1671152 0.51 0.5730587020.7073 hCV8718961 rs1654451 hCV1376266 rs1654413 0.51 0.573058702 0.7211hCV8718961 rs1654451 hCV1376342 rs1654416 0.51 0.573058702 0.5824hCV8718961 rs1654451 hCV1376359 rs2886412 0.51 0.573058702 0.7389hCV8718961 rs1654451 hCV16044361 rs2569513 0.51 0.573058702 0.9121hCV8718961 rs1654451 hCV26895257 rs2886415 0.51 0.573058702 0.8105hCV8718961 rs1654451 hCV29271569 rs1626971 0.51 0.573058702 1 hCV8718961rs1654451 hCV31722831 rs11671922 0.51 0.573058702 0.7314 hCV8718961rs1654451 hCV31722832 rs11084381 0.51 0.573058702 0.6692 hCV8718961rs1654451 hCV31722834 rs11084382 0.51 0.573058702 0.584 hCV8718961rs1654451 hCV31722835 rs11668169 0.51 0.573058702 0.6692 hCV8718961rs1654451 hCV31722836 rs11672026 0.51 0.573058702 0.7025 hCV8718961rs1654451 hCV7841075 rs1671196 0.51 0.573058702 0.6692 hCV8718961rs1654451 hCV8703249 rs1654444 0.51 0.573058702 0.9398 hCV8718961rs1654451 hCV8717752 rs1671217 0.51 0.573058702 1 hCV8718961 rs1654451hCV8717761 rs1654439 0.51 0.573058702 0.8855 hCV8718961 rs1654451hCV8717793 rs1654433 0.51 0.573058702 0.9121 hCV8718961 rs1654451hCV8717794 rs1654432 0.51 0.573058702 0.9121 hCV8718961 rs1654451hCV8717845 rs892090 0.51 0.573058702 0.8233 hCV8718961 rs1654451hCV8717846 rs892089 0.51 0.573058702 0.7314 hCV8718961 rs1654451hCV8717873 rs1613662 0.51 0.573058702 0.8233 hCV8718961 rs1654451hCV8717881 rs1654420 0.51 0.573058702 0.6692 hCV8718961 rs1654451hCV8717893 rs1671192 0.51 0.573058702 0.756 hCV8718961 rs1654451hCV8718972 rs1654447 0.51 0.573058702 0.94 hCV8718961 rs1654451hCV9490926 rs1654419 0.51 0.573058702 0.6692 hCV8911768 rs941988hCV11342529 rs1951627 0.51 0.228649809 0.3108 hCV8911768 rs941988hCV11975630 rs2065170 0.51 0.228649809 1 hCV8911768 rs941988 hCV15864094rs2068871 0.51 0.228649809 0.9425 hCV8911768 rs941988 hCV15956059rs2227592 0.51 0.228649809 1 hCV8911768 rs941988 hCV16135173 rs21463720.51 0.228649809 1 hCV8911768 rs941988 hCV16180170 rs2227589 0.510.228649809 1 hCV8911768 rs941988 hCV16290208 rs2759328 0.51 0.2286498091 hCV8911768 rs941988 hCV1681325 rs898657 0.51 0.228649809 0.288hCV8911768 rs941988 hCV1681328 rs10912647 0.51 0.228649809 0.2457hCV8911768 rs941988 hCV25600635 rs7539322 0.51 0.228649809 0.8856hCV8911768 rs941988 hCV25932979 rs16846809 0.51 0.228649809 0.5549hCV8911768 rs941988 hCV27483572 rs3791022 0.51 0.228649809 1 hCV8911768rs941988 hCV28998001 rs6425251 0.51 0.228649809 0.2457 hCV8911768rs941988 hCV29517287 rs2901747 0.51 0.228649809 0.2436 hCV8911768rs941988 hCV29989899 rs6685043 0.51 0.228649809 0.6095 hCV8911768rs941988 hCV30205817 rs10489254 0.51 0.228649809 0.5549 hCV8911768rs941988 hCV30404194 rs6691053 0.51 0.228649809 0.3572 hCV8911768rs941988 hCV30472885 rs7520441 0.51 0.228649809 0.315 hCV8911768rs941988 hCV30804119 rs10912651 0.51 0.228649809 0.2376 hCV8911768rs941988 hCV30804135 rs12078293 0.51 0.228649809 0.2457 hCV8911768rs941988 hCV30804139 rs12089930 0.51 0.228649809 0.245 hCV8911768rs941988 hCV8911729 rs941987 0.51 0.228649809 0.8292 hCV8911768 rs941988hCV9575253 rs1031751 0.51 0.228649809 0.3146 hCV8911768 rs941988hCV9575263 rs898658 0.51 0.228649809 0.2457 hCV8911768 rs941988hDV70683090 rs16846433 0.51 0.228649809 0.9425 hCV8911768 rs941988hDV70683162 rs16846526 0.51 0.228649809 1 hCV8911768 rs941988hDV70683177 rs16846546 0.51 0.228649809 1 hCV8911768 rs941988hDV70683187 rs16846561 0.51 0.228649809 1 hCV8911768 rs941988hDV70683212 rs16846593 0.51 0.228649809 0.5549 hCV8911768 rs941988hDV70683382 rs16846815 0.51 0.228649809 0.5078 hCV8911768 rs941988hDV70934851 rs17301125 0.51 0.228649809 0.2534 hCV8919444 rs4524hCV11341772 rs4589164 0.51 0.098333329 0.1285 hCV8919444 rs4524hCV11341879 rs7527703 0.51 0.098333329 0.1112 hCV8919444 rs4524hCV11341886 rs7539415 0.51 0.098333329 0.1052 hCV8919444 rs4524hCV11341964 rs12124049 0.51 0.098333329 0.1062 hCV8919444 rs4524hCV11342057 rs10919186 0.51 0.098333329 0.7473 hCV8919444 rs4524hCV11975196 rs2040444 0.51 0.098333329 0.358 hCV8919444 rs4524hCV1264276 rs17345170 0.51 0.098333329 0.1214 hCV8919444 rs4524hCV15802102 rs2420369 0.51 0.098333329 0.3671 hCV8919444 rs4524hCV15847759 rs2187952 0.51 0.098333329 1 hCV8919444 rs4524 hCV15852051rs2213867 0.51 0.098333329 0.8264 hCV8919444 rs4524 hCV15955265rs2227244 0.51 0.098333329 1 hCV8919444 rs4524 hCV16141160 rs21575970.51 0.098333329 0.1285 hCV8919444 rs4524 hCV16175730 rs2239851 0.510.098333329 1 hCV8919444 rs4524 hCV16175731 rs2239852 0.51 0.0983333290.8118 hCV8919444 rs4524 hCV16191269 rs2298909 0.51 0.098333329 0.6586hCV8919444 rs4524 hCV22274637 rs2301515 0.51 0.098333329 0.7941hCV8919444 rs4524 hCV2229795 rs723751 0.51 0.098333329 0.4376 hCV8919444rs4524 hCV2456680 rs6427193 0.51 0.098333329 0.119 hCV8919444 rs4524hCV2456690 rs6692649 0.51 0.098333329 0.1119 hCV8919444 rs4524hCV2456692 rs12128350 0.51 0.098333329 0.1136 hCV8919444 rs4524hCV2456693 rs6672589 0.51 0.098333329 0.1331 hCV8919444 rs4524hCV2456695 rs10919173 0.51 0.098333329 0.1331 hCV8919444 rs4524hCV2456709 rs17577184 0.51 0.098333329 0.1068 hCV8919444 rs4524hCV2456710 rs4656680 0.51 0.098333329 0.1112 hCV8919444 rs4524hCV2456716 rs12730053 0.51 0.098333329 0.1112 hCV8919444 rs4524hCV2456722 rs12119479 0.51 0.098333329 0.1112 hCV8919444 rs4524hCV2456729 rs12143708 0.51 0.098333329 0.1068 hCV8919444 rs4524hCV2456767 rs2014061 0.51 0.098333329 0.1287 hCV8919444 rs4524hCV2456774 rs1014965 0.51 0.098333329 0.1025 hCV8919444 rs4524hCV2456776 rs6669741 0.51 0.098333329 0.1052 hCV8919444 rs4524hCV2456780 rs7534737 0.51 0.098333329 0.1052 hCV8919444 rs4524hCV2481727 rs6670407 0.51 0.098333329 0.4176 hCV8919444 rs4524hCV2481728 rs9332665 0.51 0.098333329 0.7359 hCV8919444 rs4524hCV2481731 rs9332640 0.51 0.098333329 0.4021 hCV8919444 rs4524hCV2481732 rs12131397 0.51 0.098333329 0.3978 hCV8919444 rs4524hCV2481733 rs9332627 0.51 0.098333329 1 hCV8919444 rs4524 hCV2481738rs4656187 0.51 0.098333329 1 hCV8919444 rs4524 hCV2481741 rs3766109 0.510.098333329 1 hCV8919444 rs4524 hCV2481744 rs9332600 0.51 0.098333329 1hCV8919444 rs4524 hCV2481747 rs9332595 0.51 0.098333329 0.7683hCV8919444 rs4524 hCV2481748 rs3766110 0.51 0.098333329 0.7683hCV8919444 rs4524 hCV2481750 rs10800456 0.51 0.098333329 0.6306hCV8919444 rs4524 hCV2520857 rs12118611 0.51 0.098333329 0.1356hCV8919444 rs4524 hCV2520872 rs3766090 0.51 0.098333329 0.1059hCV8919444 rs4524 hCV2520887 rs10442644 0.51 0.098333329 0.1285hCV8919444 rs4524 hCV2521003 rs2040446 0.51 0.098333329 0.1214hCV8919444 rs4524 hCV25617181 rs9332620 0.51 0.098333329 1 hCV8919444rs4524 hCV25922120 rs9332643 0.51 0.098333329 1 hCV8919444 rs4524hCV27242356 rs12121994 0.51 0.098333329 0.1358 hCV8919444 rs4524hCV27242515 rs3818844 0.51 0.098333329 0.1009 hCV8919444 rs4524hCV27242533 rs2138898 0.51 0.098333329 0.1023 hCV8919444 rs4524hCV27242706 rs7524348 0.51 0.098333329 0.1331 hCV8919444 rs4524hCV27242809 rs9332630 0.51 0.098333329 0.3659 hCV8919444 rs4524hCV27490260 rs3820060 0.51 0.098333329 0.8118 hCV8919444 rs4524hCV275164 rs12140572 0.51 0.098333329 0.1278 hCV8919444 rs4524hCV27928247 rs4656182 0.51 0.098333329 0.1068 hCV8919444 rs4524hCV27972646 rs4656677 0.51 0.098333329 0.1112 hCV8919444 rs4524hCV288901 rs4656671 0.51 0.098333329 0.1112 hCV8919444 rs4524hCV29621699 rs9332619 0.51 0.098333329 1 hCV8919444 rs4524 hCV30018856rs6701330 0.51 0.098333329 0.7509 hCV8919444 rs4524 hCV30036717rs9332653 0.51 0.098333329 0.102 hCV8919444 rs4524 hCV30144962rs10158595 0.51 0.098333329 0.7453 hCV8919444 rs4524 hCV30234691rs6662593 0.51 0.098333329 0.9762 hCV8919444 rs4524 hCV30433255rs9332655 0.51 0.098333329 0.9135 hCV8919444 rs4524 hCV30504827rs9332608 0.51 0.098333329 0.1235 hCV8919444 rs4524 hCV30577322rs7516248 0.51 0.098333329 0.1052 hCV8919444 rs4524 hCV32141090rs12039443 0.51 0.098333329 0.1294 hCV8919444 rs4524 hCV32141333rs10800446 0.51 0.098333329 0.0998 hCV8919444 rs4524 hCV32141337rs10919164 0.51 0.098333329 0.115 hCV8919444 rs4524 hCV32141359rs12022776 0.51 0.098333329 0.0998 hCV8919444 rs4524 hCV32141374rs10919174 0.51 0.098333329 0.1582 hCV8919444 rs4524 hCV32398607rs4656658 0.51 0.098333329 0.1214 hCV8919444 rs4524 hCV328321 rs93326670.51 0.098333329 1 hCV8919444 rs4524 hCV337817 rs9332586 0.510.098333329 0.1619 hCV8919444 rs4524 hCV340605 rs1557572 0.510.098333329 0.7416 hCV8919444 rs4524 hCV341935 rs4656685 0.510.098333329 0.9762 hCV8919444 rs4524 hCV342590 rs6030 0.51 0.0983333290.847 hCV8919444 rs4524 hCV475606 rs17349579 0.51 0.098333329 0.105hCV8919444 rs4524 hCV70275 rs4656687 0.51 0.098333329 0.8118 hCV8919444rs4524 hCV8006091 rs6656463 0.51 0.098333329 0.1151 hCV8919444 rs4524hCV8697038 rs961403 0.51 0.098333329 0.1052 hCV8919444 rs4524 hCV8697043rs1517747 0.51 0.098333329 0.1582 hCV8919444 rs4524 hCV8919166 rs12001390.51 0.098333329 0.1536 hCV8919444 rs4524 hCV8919279 rs1200079 0.510.098333329 0.2649 hCV8919444 rs4524 hCV8919424 rs974793 0.510.098333329 0.9762 hCV8919444 rs4524 hCV8919429 rs970741 0.510.098333329 0.9762 hCV8919444 rs4524 hCV8919436 rs916438 0.510.098333329 0.8118 hCV8919444 rs4524 hCV8919438 rs1557570 0.510.098333329 0.7402 hCV8919444 rs4524 hCV8919441 rs6032 0.51 0.0983333291 hCV8919444 rs4524 hCV8919442 rs4525 0.51 0.098333329 1 hCV8919444rs4524 hCV8919446 rs6021 0.51 0.098333329 1 hCV8919444 rs4524 hCV8919450rs6017 0.51 0.098333329 1 hCV8919444 rs4524 hCV8919451 rs6016 0.510.098333329 0.9762 hCV8919444 rs4524 hCV9945852 rs1121789 0.510.098333329 1 hCV8919444 rs4524 hDV70942075 rs17349271 0.51 0.0983333290.1214 hCV8919444 rs4524 hDV70942101 rs17349439 0.51 0.098333329 0.1214hCV8919444 rs4524 hDV77030721 rs4656664 0.51 0.098333329 0.1224hCV9102827 rs3795733 hCV11258640 rs6427323 0.51 0.60489105 0.7384hCV9102827 rs3795733 hCV25989540 rs6682716 0.51 0.60489105 0.6304hCV9102827 rs3795733 hCV26627664 rs3795727 0.51 0.60489105 0.7186hCV9102827 rs3795733 hCV26627665 rs2365714 0.51 0.60489105 0.7186hCV9102827 rs3795733 hCV26627679 rs7536235 0.51 0.60489105 0.7186hCV9102827 rs3795733 hCV31431594 rs12567958 0.51 0.60489105 0.863hCV9102827 rs3795733 hCV31431603 rs11264508 0.51 0.60489105 0.7186hCV9102827 rs3795733 hCV31431609 rs12742817 0.51 0.60489105 0.7186hCV9102827 rs3795733 hCV31431620 rs12023410 0.51 0.60489105 0.714hCV9102827 rs3795733 hCV31431621 rs11576266 0.51 0.60489105 1 hCV9102827rs3795733 hCV9102814 rs879461 0.51 0.60489105 0.8863 hCV9102827rs3795733 hCV9102822 rs4661052 0.51 0.60489105 0.8863 hCV9102827rs3795733 hCV9102823 rs12024215 0.51 0.60489105 0.7508 hCV9102827rs3795733 hCV9102829 rs3795732 0.51 0.60489105 0.8859 hCV9102827rs3795733 hCV9102841 rs4661188 0.51 0.60489105 0.8863 hCV9102827rs3795733 hCV9102976 rs10908509 0.51 0.60489105 0.6291 hCV916107rs670659 hCV1874947 rs494075 0.51 0.426900693 0.4398 hCV916107 rs670659hCV25653735 rs7520707 0.51 0.426900693 0.5479 hCV916107 rs670659hCV26887401 rs10802916 0.51 0.426900693 0.4941 hCV916107 rs670659hCV26887441 rs9786932 0.51 0.426900693 0.5809 hCV916107 rs670659hCV26887461 rs4660023 0.51 0.426900693 0.7128 hCV916107 rs670659hCV26887463 rs6680767 0.51 0.426900693 0.7121 hCV916107 rs670659hCV26887464 rs6669640 0.51 0.426900693 0.6131 hCV916107 rs670659hCV26887465 rs10802919 0.51 0.426900693 0.5881 hCV916107 rs670659hCV31714435 rs12143076 0.51 0.426900693 0.463 hCV916107 rs670659hCV31714436 rs12132113 0.51 0.426900693 0.43 hCV916107 rs670659hCV31714438 rs12731839 0.51 0.426900693 0.4771 hCV916107 rs670659hCV31714442 rs12119557 0.51 0.426900693 0.4359 hCV916107 rs670659hCV31714442 rs12758552 0.51 0.426900693 0.4423 hCV916107 rs670659hCV31714443 rs12758552 0.51 0.426900693 0.4423 hCV916107 rs670659hCV31714447 rs10926387 0.51 0.426900693 0.5544 hCV916107 rs670659hCV31714470 rs10926390 0.51 0.426900693 0.4745 hCV916107 rs670659hCV31714471 rs10926391 0.51 0.426900693 0.4562 hCV916107 rs670659hCV916106 rs575226 0.51 0.426900693 1

TABLE 4 Association of statin with VT in 27 SNP genotype subgroups inMEGA statin Com- OR statin non- statin statin p(int) parison Gene Risk(95% users, user, users, nonusers, statin* for p(int) hCV # Symbol (SNPrs #) Allele Subgroup Cl) P cases cases controls controls SNP statin*SNPhCV11286902 LOC400499 G GG 0.34  4E−04 14 641 54 (0.22) 793 (0.2) 0.010GG vs. (rs12932948) (0.19-0.62) (0.11) (0.19) AA GA 0.6 0.001 62 (0.5)1668 124 (0.5) 1907 (0.47) 0.168 GA vs. (0.43-0.82) (0.48) AA AA 0.780.208 47 1142 69 (0.28) 1352 (0.33) ref (0.53-1.15) (0.38) (0.33) GA +GG 0.52 5.E−06 0.044 GA + (0.4-0.69) GG vs. AA GA + AA 0.66  9E−04 0.029GG vs. (0.52-0.85) GA + AA hCV11786258 KLKB1 A AA 0.35  7E−04 15 700 41(0.16) 642 (0.15) 0.035 AA vs. (rs4253303) (0.19-0.64) (0.12) (0.2) GGAG 0.57  6E−04 61 1742 122 (0.47) 2007 (0.48) 0.384 AG vs. (0.42-0.79)(0.49) (0.49) GG GG 0.73 0.095 48 1114 94 (0.37) 1552 (0.37) ref(0.51-1.06) (0.39) (0.31) AG + AA 0.51 3.E−06 0.139 AG + (0.39-0.68) AAvs. GG AG + GG 0.63  2E−04 0.056 AA vs. (0.5-0.81) AG + GG hCV12066124F11 C CC 0.38 3.E−05 27 1245 68 (0.26) 1138 (0.27) 0.136 CC vs.(rs2036914) (0.24-0.6) (0.22) (0.35) TT CT 0.66 0.008 72 1679 130 (0.5)2066 (0.49) 0.662 CT vs. (0.49-0.9) (0.59) (0.47) TT TT 0.64 0.077 23623 61 (0.24) 994 (0.24) ref (0.39-1.05) (0.19) (0.18) CT + CC 0.553.E−06 0.740 CT + (0.43-0.71) CC vs. TT CT + TT 0.66 0.001 0.022 CC vs.(0.51-0.85) CT + TT hCV12092542 CASP5 T TT 0.75 0.189 39 1025 54 (0.26)1083 (0.31) 0.602 TT vs. (rs507879) (0.49-1.15) (0.33) (0.3) CC TC 0.471.E−05 52 1704 116 (0.57) 1742 (0.49) 0.027 TC vs. (0.34-0.66) (0.44)(0.51) CC CC 0.94 0.815 28 638 35 (0.17) 725 (0.2) ref (0.56-1.58)(0.24) (0.19) TC + TT 0.56 2.E−05 0.089 TC + (0.43-0.73) TT vs. CC TC +CC 0.57  1E−04 0.225 TT vs. (0.43-0.76) TC + CC hCV15968043 CYP4V2 A AA0.33  3E−04 15 739 44 (0.17) 693 (0.17) 0.040 AA vs. (rs2292423)(0.18-0.61) (0.12) (0.21) TT AT 0.61 0.002 64 1755 122 (0.48) 2021(0.48) 0.704 AT vs. (0.45-0.84) (0.53) (0.5) TT TT 0.67 0.038 42 1021 90(0.35) 1456 (0.35) ref (0.46-0.98) (0.35) (0.29) AT + AA 0.53 8.E−060.291 AT + (0.4-0.7) AA vs. TT AT + TT 0.63  2E-04 0.038 AA vs.(0.5-0.81) AT + TT hCV16171263 PRLR G GA 0.2 0.01 3 207 20 (0.08) 231(0.06) 0.043 GA vs. (rs16871473) (0.06-0.68) (0.02) (0.06) AA AA 0.612.E−05 122 3335 238 (0.92) 3951 (0.94) ref (0.49-0.77) (0.98) (0.94)GA + GG 0.2 0.01 0.041 GA + (0.06-0.68) GG vs. AA GA + AA 0.58 2.E−06n/a (0.47-0.73) hCV1859855 GOLGA3 C CC 0.16 0.004 3 232 14 (0.05) 175(0.04) 0.049 CC vs. (rs2291260) (0.04-0.56) (0.02) (0.07) TT CT 0.60.005 48 1207 96 (0.37) 1453 (0.35) 0.899 CT vs. (0.42-0.86) (0.39)(0.34) TT TT 0.6  8E−04 71 2088 (0.59) 147 (0.57) 2522 (0.61) ref(0.45-0.81) (0.58) CT + CC 0.52  2E−04 0.631 CT + (0.37-0.73) CC vs. TTCT + TT 0.6 1.E−05 0.045 CC vs. (0.48-0.76) CT + TT hCV1948599 CSMD2 AAA 0.51 0.008 24 765 (0.22) 56 (0.22) 945 (0.22) 0.198 AA vs. (rs504527)(0.31-0.84) (0.2) CC AC 0.49 2.E−05 53 1718 (0.49) 137 (0.53) 2113 (0.5)0.044 AC vs. (0.35-0.68) (0.43) CC CC 0.86 0.44 45 1005 (0.29) 64 (0.25)1144 (0.27) ref (0.58-1.27) (0.37) AC + AA 0.49 4.E−07 0.044 AC +(0.38-0.65) AA vs. CC AC + CC 0.61 1.E−04 0.740 AA vs. (0.47-0.78) AC +CC hCV1952126 (rs7223784) A AA 0.54 9.E−05 64 1976 (0.56) 138 (0.53)2258 (0.54) 0.019 AA vs. (0.4-0.74) (0.52) CC AC 0.52  5E−04 43 1343(0.38) 101 (0.39) 1598 (0.38) 0.018 AC vs. (0.36-0.75) (0.35) CC CC 1.210.584 17 236 (0.07) 19 (0.07) 338 (0.08) ref (0.61-2.42) (0.14) AC + AA0.53 2.E−07 0.014 AC + (0.42-0.67) AA vs. CC AC + CC 0.62 0.003 0.507 AAvs. (0.45-0.85) AC + CC hCV22272267 KLKB1 A AA 0.41  2E−04 27 1141(0.32) 66 (0.26) 1092 (0.26) 0.141 AA vs. (rs3733402) (0.26-0.65) (0.22)GG AG 0.67 0.01 70 1723 (0.49) 126 (0.49) 2112 (0.5) 0.793 AG vs.(0.5-0.91) (0.56) GG GG 0.67 0.085 28 680 (0.19) 64 (0.25) 985 (0.24)ref (0.42-1.06) (0.22) AG + AA 0.57 2.E−05 0.665 AG + (0.44-0.74) AA vs.GG AG + GG 0.67 0.002 0.045 AA vs. (0.52-0.86) AG + GG hCV2434510 RNASE7C CC 0.8 0.863 1 46 (0.01) 2 (0.01) 44 (0.01) 0.804 CC vs. (rs1243469)(0.07-9.85) (0.01) TT CT 0.35  2E−04 17 699 (0.2) 55 (0.22) 797 (0.19)0.047 CT vs. (0.2-0.61) (0.14) TT TT 0.66  9E−04 106 2774 (0.79) 196(0.77) 3324 (0.8) ref (0.52-0.84) (0.85) CT + CC 0.36  3E−04 0.046 CT +(0.21-0.62) CC vs. TT CT + TT 0.59 4.E−06 0.872 CC vs. (0.47-0.74) CT +TT hCV25610857 (rs8176693) T TT 1.61 0.709 2 31 (0.01) 1 (0) 28 (0.01)0.307 TT vs. (0.13-19.25) (0.02) CC TC 0.92 0.755 31 604 (0.17) 34(0.13) 546 (0.13) 0.081 TC vs. (0.55-1.54) (0.25) CC CC 0.5 9.E−08 892886 (0.82) 224 (0.86) 3629 (0.86) ref (0.39-0.64) (0.73) TC + TT 0.940.822 0.058 TC + (0.57-1.55) TT vs. CC TC + CC 0.57 8.E−07 0.349 TT vs.(0.45-0.71) TC + CC hCV25631989 ATF6 T TT 0.98 0.985 1 23 (0.01) 2(0.01) 37 (0.01) 0.659 TT vs. (rs1135983) (0.07-12.9) (0.01) CC TC 1.090.725 32 505 (0.14) 37 (0.14) 604 (0.14) 0.007 TC vs. (0.66-1.8) (0.26)CC CC 0.49 5.E−08 88 2963 (0.85) 218 (0.85) 3552 (0.85) ref (0.38-0.63)(0.73) TC + TT 1.09 0.723 0.006 TC vs. (0.67-1.78) CC TC + CC 0.582.E−06 0.749 TT vs. (0.46-0.72) TC + CC hCV26175114 TUBA4A G GG 1.190.854 3 83 (0.02) 2 (0.01) 73 (0.02) 0.414 GG vs. (rs3731892)(0.18-7.89) (0.02) AA GA 0.28  4E−04 10 638 (0.18) 44 (0.17) 749 (0.18)0.024 GA vs. (0.14-0.57) (0.08) AA AA 0.62  1E−04 109 2785 (0.79) 210(0.82) 3336 (0.8) ref (0.49-0.79) (0.89) GA + GG 0.34  9E−04 0.054 GA +(0.18-0.64) GG vs. AA GA + AA 0.57 9.E−07 0.351 GG vs. (0.45-0.71) GA +AA hCV27474984 PIK3R1 A AA 0.64 0.079 26 773 (0.22) 50 (0.2) 876 (0.21)0.134 AA vs. (rs3756668) (0.39-1.05) (0.21) GG AG 0.41 9.E−08 54 1761(0.5) 144 (0.57) 1977 (0.47) 0.002 AG vs. (0.3-0.57) (0.44) GG GG 0.980.94 43 985 (0.28) 60 (0.24) 1310 (0.31) ref (0.66-1.48) (0.35) AG + AA0.47 4.E−08 0.003 AG + (0.36-0.62) AA vs. GG AG + GG 0.57 1.E−05 0.896AA vs. (0.44-0.73) AG + GG hCV27502514 KLF3 A AA 2.69 0.118 9 97 (0.03)4 (0.02) 109 (0.03) 0.011 AA vs. (rs3796533) (0.78-9.27) (0.07) GG AG0.57 0.008 36 1005 (0.28) 69 (0.27) 1155 (0.28) 0.502 AG vs. (0.37-0.87)(0.29) GG GG 0.53 5.E−06 79 2450 (0.69) 185 (0.72) 2910 (0.7) ref(0.4-0.7) (0.64) AG + AA 0.68 0.048 0.162 AG + (0.46-1) AA vs. GG AG +GG 0.54 1.E−07 0.014 AA vs. (0.43-0.68) AG + GG hCV3054799 KIF6 G GG0.52 0.032 17 515 (0.14) 37 (0.14) 587 (0.14) 0.408 GG vs. (rs20455)(0.29-0.95) (0.14) AA GA 0.83 0.261 66 1581 (0.44) 96 (0.37) 1901 (0.45)0.003 GA vs. (0.6-1.15) (0.53) AA AA 0.41 1.E−06 42 1462 (0.41) 125(0.48) 1710 (0.41) ref (0.28-0.58) (0.34) GA + GG 0.74 0.041 0.006 GA +(0.56-0.99) GG vs. AA GA + AA 0.59 2.E−05 0.763 GG vs. (0.47-0.75) GA +AA hCV3054805 KIF6 G GG 0.57 0.035 23 666 (0.19) 46 (0.18) 741 (0.18)0.181 GG vs. (rs2894424) (0.34-0.96) (0.19) CC GC 0.78 0.134 66 1621(0.46) 104 (0.41) 2019 (0.48) 0.003 GC vs. (0.57-1.08) (0.55) CC CC 0.383.E−06 32 1204 (0.34) 106 (0.41) 1431 (0.34) ref (0.25-0.57) (0.26) GC +GG 0.72 0.018 0.005 GC + (0.55-0.95) GG vs. CC GC + CC 0.58 2.E−05 0.960GG vs. (0.45-0.74) GC + CC hCV3054808 KIF6 A AA 0.49 0.015 18 584 (0.17)42 (0.16) 675 (0.16) 0.580 AA vs. (rs9462535) (0.28-0.87) (0.15) CC AC0.8 0.169 64 1598 (0.46) 99 (0.39) 1957 (0.47) 0.009 AC vs. (0.57-1.1)(0.52) CC CC 0.43 1.E−05 40 1313 (0.38) 116 (0.45) 1565 (0.37) ref(0.3-0.63) (0.33) AC + AA 0.71 0.016 0.024 AC + (0.53-0.94) AA vs. CCAC + CC 0.6 4.E−05 0.612 AA vs. (0.47-0.77) AC + CC hCV3054813 KIF6 G GG0.48 0.011 19 593 (0.17) 44 (0.17) 663 (0.16) 0.561 GG vs. (rs9471077)(0.28-0.84) (0.16) AA GA 0.82 0.246 65 1606 (0.46) 98 (0.38) 1977 (0.47)0.005 GA vs. (0.6-1.14) (0.53) AA AA 0.41 5.E−06 38 1294 (0.37) 115(0.45) 1555 (0.37) ref (0.28-0.6) (0.31) GA + GG 0.72 0.021 0.015 GA +(0.54-0.95) GG vs. AA GA + AA 0.6 5.E−05 0.531 GG vs. (0.47-0.77) GA +AA hCV3054822 (rs11751357) A AA 0.44 0.074 7 270 (0.08) 17 (0.07) 298(0.07) 0.819 AA vs. (0.18-1.08) (0.06) TT AT 0.9 0.542 64 1362 (0.39) 89(0.35) 1646 (0.39) 0.002 AT vs. (0.65-1.26) (0.52) TT TT 0.42 2.E−07 511852 (0.53) 151 (0.59) 2248 (0.54) ref (0.3-0.58) (0.42) AT + AA 0.820.2 0.004 AT + (0.6-1.11) AA vs. TT AT + TT 0.6 1.E−05 0.620 AA vs.(0.48-0.75) AT+TT hCV3230113 CYP4V2 T TT 0.36 2.E−05 25 1041 (0.3) 67(0.26) 990 (0.24) 0.060 TT vs. (rs1053094) (0.22-0.57) (0.21) AA TA 0.670.012 64 1739 (0.5) 119 (0.46) 2132 (0.51) 0.937 TA vs. (0.49-0.92)(0.53) AA AA 0.69 0.096 32 732 (0.21) 73 (0.28) 1078 (0.26) ref(0.45-1.07) (0.26) TA + TT 0.54 5.E−06 0.464 TA vs. (0.42-0.71) AA TA +AA 0.67 0.002 0.024 TT vs. (0.52-0.86) TA + AA hCV470708 THBS2 T TT 0.820.52 19 373 (0.1) 27 (0.11) 400 (0.1) 0.878 TT vs. (rs10945408)(0.44-1.51) (0.15) GG TG 0.4 8.E−07 42 1519 (0.43) 124 (0.48) 1823(0.43) 0.021 TG vs. (0.28-0.58) (0.34) GG GG 0.73 0.061 64 1673 (0.47)106 (0.41) 1982 (0.47) ref (0.53-1.01) (0.51) TG + TT 0.48 3.E−06 0.068TG vs. (0.35-0.65) GG TG + GG 0.55 1.E−06 0.338 TT vs. (0.44-0.7) TG +GG hCV491830 EPS8L2 T TT 0.48  4E−04 34 1167 (0.33) 81 (0.32) 1302(0.31) 0.036 TT vs. (rs3087546) (0.32-0.72) (0.27) CC TC 0.55  2E−04 621700 (0.48) 136 (0.53) 2020 (0.48) 0.070 TC vs. (0.4-0.75) (0.5) CC CC0.97 0.919 29 666 (0.19) 40 (0.16) 846 (0.2) ref (0.59-1.6) (0.23) TC +TT 0.52 3.E−07 0.035 TC vs. (0.41-0.67) CC TC + CC 0.64  9E−04 0.236 TTvs. (0.49-0.83) TC + CC hCV8241630 F11 A AA 0.44 0.005 18 726 (0.21) 38(0.15) 627 (0.15) 0.070 AA vs. (rs925451) (0.24-0.78) (0.15) GG AG 0.526.E−05 58 1729 (0.49) 125 (0.48) 1922 (0.46) 0.116 AG vs. (0.37-0.71)(0.47) GG GG 0.78 0.175 47 1079 (0.31) 95 (0.37) 1650 (0.39) ref(0.54-1.12) (0.38) AG + AA 0.49 9.E−07 0.052 AG + (0.37-0.65) AA vs. GGAG + GG 0.61 7.E−05 0.203 AA vs. (0.48-0.78) AG + GG hCV8919444 F5 T TT0.66 0.004 86 2176 (0.61) 135 (0.53) 2295 (0.55) 0.110 TT vs. (rs4524)(0.5-0.87) (0.69) CC TC 0.5  5E−04 36 1189 (0.34) 104 (0.41) 1589 (0.38)0.272 TC vs. (0.34-0.74) (0.29) CC CC 0.2 0.034 2 181 (0.05) 17 (0.07)304 (0.07) ref (0.05-0.89) (0.02) TC + TT 0.6 9.E−06 0.150 TC vs.(0.48-0.75) CC TC + CC 0.46 6.E−05 0.065 TT vs. (0.32-0.68) TC + CChDV68530934 TF 1208 I/D A AA 0.78 0.281 33 775 (0.22) 49 (0.19) 876(0.21) 0.036 AA vs. (hDV68530934) (0.49-1.23) (0.26) CC AC 0.62 0.002 661777 (0.5) 127 (0.49) 2081 (0.5) 0.099 AC vs. (0.45-0.84) (0.53) CC CC0.39 6.E−05 26 1004 (0.28) 83 (0.32) 1242 (0.3) ref (0.25-0.62) (0.21)AC + AA 0.66 0.002 0.046 AC + (0.51-0.86) AA vs. CC AC + CC 0.53 1.E−060.153 AA vs. (0.41-0.68) AC + CC 27 SNPs (shown above in Table 4) had ap(int) statin*SNP <0.05 (Wald test) in any model. p(int) statin*SNP: Pvalue <0.05 (Wald test) for statin*SNP interaction term (ModelFormula:VTE~SNP + statin user or nonuser + SNP*statin + age + sex) is specificfor the subgroup shown. Endpoint: VT (including DVT and PE) Parameter:statin use (statin users or statin nonusers)

TABLE 5 Association of 75 SNPs with VT risk in statin user and statinnonuser subgroups in MEGA (additive P < 0.05). p(int) Allele1 Allele2Geno- statin*SNP marker Gene Risk OR (allele (allele Genotype ControlGenotype Case Control type Control (additive) (hCV #) (SNP rs #) Alleleparameter Strata (95% Cl) P-value freq) freq) 1 Case 1 1 2 2 2 3 Case 33 0.034221851 hCV8919444 F5 T T_vs_C statin_0 1.26 5E−10 C(0.26) T(0.74)CC 181 304 CT 1189 1589 TT 2176 2295 (rs4524) (1.17-1.36) statin_1 1.950.001 C(0.27) T(0.73) CC 2 17 CT 36 104 TT 86 135 (1.31-2.93) 0.04127343hCV11786258 KLKB1 A A_vs_G statin_0 1.23 3E−10 A(0.39) G(0.61) AA 700642 AG 1742 2007 GG 1114 1552 (rs4253303) (1.15-1.31) statin_1 0.88 0.41A(0.4) G(0.6) AG 61 122 GG 48 94 AA 15 41 (0.64-1.2) 0.046438831hCV8241630 F11 A A_vs_G statin_0 1.34 5E−19 A(0.38) G(0.62) AA 726 627AG 1729 1922 GG 1079 1650 (rs925451) (1.26-1.43) statin_1 0.96 0.805A(0.39) G(0.61) AA 18 38 AG 58 125 GG 47 95 (0.7-1.32) 0.047140799hCV25610857 (rs8176693) T T_vs_C statin_0 1.35 3E−07 C(0.93) T(0.07) CC2886 3629 CT 604 546 TT 31 28 (1.2-1.51) statin_1 2.27 0.002 C(0.93)T(0.07) CC 89 224 CT 31 34 TT 2 1 (1.37-3.77) 0.048367213 hCV491830EPS8L2 T T_vs_C statin_0 1.07 0.046 C(0.45) T(0.55) CC 666 846 CT 17002020 TT 1167 1302 (rs3087546) (1-1.14) statin_1 0.76 0.095 C(0.42)T(0.58) CC 29 40 CT 62 136 TT 34 81 (0.56-1.05) 0.06328739 hCV3230113CYP4V2 T T_vs_A statin_0 1.25 1E−11 A(0.51) T(0.49) AA 732 1078 AT 17392132 TT 1041 990 (rs1053094) (1.17-1.33) statin_1 0.93 0.641 A(0.51)T(0.49) AA 32 73 AT 64 119 TT 25 67 (0.69-1.26) 0.065533427 hCV15968043CYP4V2 A A_vs_T statin_0 1.23 1E−10 A(0.41) T(0.59) AA 739 693 AT 17552021 TT 1021 1456 (rs2292423) (1.16-1.32) statin_1 0.91 0.547 A(0.41)T(0.59) AA 15 44 AT 64 122 TT 42 90 (0.66-1.25) 0.069827287 hCV27474984PIK3R1 A A_vs_G statin_0 1.09 0.007 A(0.45) G(0.55) AA 773 876 AG 17611977 GG 985 1310 (rs3756668) (1.02-1.16) statin_1 0.81 0.195 A(0.48)G(0.52) AA 26 50 AG 54 144 GG 43 60 (0.59-1.11) 0.078778864 hCV11633415LOC730144 T T_vs_C statin_0 1.17 0.011 C(0.08) T(0.92) CC 25 21 CT 431616 TT 3105 3561 (rs4262503) (1.04-1.32) statin_1 0.69 0.201 C(0.07)T(0.93) CT 23 35 TT 101 224 0 0 0 (0.38-1.22) 0.09822195 hCV2442143ASAH1 T T_vs_C statin_0 0.92 0.013 C(0.51) T(0.49) CC 996 1106 CT 17072065 TT 791 1032 (rs12544854) (0.87-0.98) statin_1 1.2 0.242 C(0.54)T(0.46) CC 32 73 CT 57 134 TT 32 50 (0.88-1.64) 0.09898811 hCV12066124F11 C C_vs_T statin_0 1.32 5E-18 C(0.52) T(0.48) CC 1245 1138 CT 16792066 TT 623 994 (rs2036914) (1.24-1.41) statin_1 1 0.999 C(0.51) T(0.49)CC 27 68 CT 72 130 TT 23 61 (0.73-1.37) 0.10233127 hCV9102827 GPATCH4 CC_vs_T statin_0 1.09 0.015 C(0.26) T(0.74) CC 324 309 CT 1267 1318 TT1857 2113 (rs3795733) (1.02-1.17) statin_1 1.45 0.031 C(0.22) T(0.78) CC15 13 CT 43 74 TT 63 138 (1.04-2.04) 0.110882818 hCV1952126 (rs7223784)A A_vs_C statin_0 1.08 0.027 A(0.73) C(0.27) AA 1976 2258 AC 1343 1598CC 236 338 (1.01-1.16) statin_1 0.83 0.248 A(0.73) C(0.27) AA 64 138 AC43 101 CC 17 19 (0.6-1.14) 0.121999557 hCV27859399 ABO C C_vs_G statin_01.28 3E−06 C(0.09) G(0.91) CC 54 37 CG 690 683 GG 2780 3480 (rs7853989)(1.16-1.42) statin_1 1.87 0.009 C(0.09) G(0.91) CC 2 2 CG 34 43 GG 86213 (1.17-2.99) 0.122240353 hCV3230038 F11 T T_vs_C statin_0 1.36 1E−20C(0.6) T(0.4) CC 958 1513 CT 1752 1986 TT 812 704 (rs2289252)(1.27-1.44) statin_1 1.05 0.757 C(0.61) T(0.39) CC 43 96 CT 59 123 TT 2040 (0.77-1.43) 0.126690785 hcV22272267 KLKB1 A A_vs_G statin_0 1.239E−11 A(0.51) G(0.49) AA 1141 1092 AG 1723 2112 GG 680 985 (rs3733402)(1.16-1.32) statin_1 0.97 0.822 A(0.5) G(0.5) AA 27 66 AG 70 126 GG 2864 (0.71-1.31) 0.129651976 hCV27477533 (rs3756008) T T_vs_A statin_01.32 9E-18 A(0.61) T(0.39) AA 1029 1560 AT 1755 1960 TT 773 677(1.24-1.41) statin_1 1.03 0.84 A(0.6) T(0.4) AA 43 91 AT 61 126 TT 21 41(0.76-1.41) 0.135285269 hCV16182835 PTPN21 G G_vs_A statin_0 1.11 0.003A(0.68) G(0.32) AA 1501 1930 AG 1586 1846 GG 405 422 (rs2274736)(1.03-1.18) statin_1 0.85 0.336 A(0.63) G(0.37) AA 52 102 AG 59 121 GG11 33 (0.61-1.18) 0.142757821 hCV15793897 KLKB1 G G_vs_A statin_0 1.261E−05 A(0.11) G(0.89) AA 26 69 AG 590 800 GG 2943 3331 (rs3087505)(1.14-1.4) statin_1 0.91 0.674 A(0.12) G(0.88) AA 2 7 AG 28 46 GG 95 206(0.58-1.41) 0.154022293 hCV916107 LOC729138 C C_vs_T statin_0 1.11 0.002C(0.64) T(0.36) CC 1540 1725 CT 1618 1904 TT 375 544 (rs670659)(1.04-1.19) statin_1 0.87 0.417 C(0.68) T(0.32) CC 50 118 CT 60 111 TT13 26 (0.63-1.21) 0.164073369 hCV27474895 F11 A A_vs_C statin_0 1.341E−19 A(0.4) C(0.6) AA 824 711 AC 1743 1975 CC 977 1509 (rs3756011)(1.26-1.43) statin_1 1.06 0.702 A(0.4) C(0.6) AA 21 40 AC 60 126 CC 4293 (0.78-1.45) 0.179080773 hCV25474413 F11 C C_vs_A statin_0 1.3 3E−16A(0.52) C(0.48) AA 729 1140 AC 1733 2072 CC 1078 995 (rs3822057)(1.22-1.39) statin_1 1.04 0.808 A(0.52) C(0.48) AA 27 69 AC 71 131 CC 2559 (0.76-1.42) 0.213897396 hCV31523650 AKT3 T T_vs_C statin_0 1.12 0.003C(0.8) T(0.2) CC 2198 2738 CT 1170 1277 TT 179 183 (rs12048930)(1.04-1.21) statin_1 0.88 0.516 C(0.78) T(0.22) CC 79 160 CT 41 83 TT 415 (0.61-1.28) 0.224108979 hCV16180170 SERPINC1 T T_vs_C statin_0 1.243E−05 C(0.91) T(0.09) CC 2791 3443 CT 697 698 TT 53 40 (rs227589)(1.12-1.38) statin_1 1.71 0.029 C(0.92) T(0.08) CC 94 219 CT 29 36 TT 23 (1.06-2.76) 0.229850466 hCV1859855 GOLGA3 C C_vs_T statin_0 1.12 0.004C(0.22) T(0.78) CC 232 175 CT 1207 1453 TT 2088 2522 (rs2291260)(1.04-1.21) statin_1 0.88 0.507 C(0.24) T(0.76) CC 3 14 CT 48 96 TT 71147 (0.6-1.28) 0.278514601 hCV1376266 GP6 A A_vs_T statin_0 0.89 0.007A(0.2) T(0.8) AA 122 165 AT 1043 1351 TT 2346 2678 (rs1654413)(0.83-0.97) statin_1 1.11 0.591 A(0.19) T(0.81) AA 5 11 AT 40 76 TT 77172 (0.76-1.62) 0.285044775 hCV3230096 CYP4V2 T T_vs_C statin_0 1.22IE−09 C(0.59) T(0.41) CC 1036 1442 CT 1750 2029 TT 774 724 (rs3817184)(1.14-1.3) statin_1 1.03 0.864 C(0.58) T(0.42) CC 40 88 CT 63 124 TT 2247 (0.76-1.39) 0.288005598 hCV16170613 MET G G_vs_A statin_0 1.2 0.037A(0.97) G(0.03) AA 3258 3822 AG 253 252 GG 7 3 (rs2237712) (1.01-1.43)statin_1 0.81 0.559 A(0.95) G(0.05) AA 113 222 AG 11 25 GG 0 1(0.39-1.66) 0.288035569 hCV2532034 F13B G G_vs_A statin_0 1.13 0.022A(0.91) G(0.09) AA 2803 3455 AG 598 647 GG 51 51 (rs6003) (1.02-1.26)statin_1 1.53 0.133 A(0.94) G(0.06) AA 101 225 AG 19 30 GG 2 1(0.88-2.65) 0.030357106 hCV2915511 OBSL1 C C_vs_T statin_0 1.18 0.036C(0.04) T(0.96) CC 28 11 CT 253 285 TT 3263 3897 (rs627530) (1.01-1.38)statin_1 1.84 0.15 C(0.03) T(0.97) CT 11 13 TT 112 244 0 0 0 (0.8-4.25)0.31836145 hCV8726802 F2 A A_vs_G statin_0 2.66 1E−13 A(0.01) G(0.99) AA1 0 AG 186 86 GG 3344 4104 (rs1799963) (2.05-3.44) statin_1 1.23 0.784A(0.01) G(0.99) AG 3 5 GG 120 252 0 0 0 (0.29-5.25) 0.343434006hCV2590858 ADCY9 C C_vs_T statin_0 1.08 0.037 C(0.73) T(0.27) CC 19392199 CT 1319 1530 TT 217 317 (rs2230738) (1-1.16) statin_1 0.91 0.592C(0.76) T(0.24) CC 69 145 CT 48 91 TT 8 14 (0.64-1.29) 0.345514722hCV2303891 APOH C C_vs_G statin_0 1.26 0.002 C(0.94) G(0.06) CC 32493730 CG 300 456 GG 10 5 (rs1801690) (1.08-1.45) statin_1 0.89 0.743C(0.95) G(0.05) CC 112 235 CG 13 22 GG 0 1 (0.45-1.78) 0.35994798hCV8911768 SERPINC1 T T_vs_C statin_0 1.24 3E−05 C(0.91) T(0.09) CC 27693458 CT 696 707 TT 55 42 (rs941988) (1.12-1.38) statin_1 1.59 0.066C(0.92) T(0.08) CC 93 220 CT 28 36 TT 1 3 (0.97-2.62) 0.367055136hCV11503470 (rs1800788) T T_vs_C statin_0 1.21 4E−07 C(0.79) T(0.21) CC2057 2674 CT 1291 1325 TT 211 205 (1.13-1.31) statin_1 1.02 0.889C(0.76) T(0.24) CC 70 149 CT 46 92 TT 8 17 (0.72-1.45) 0.367169692hCV22273419 GP6 C C_vs_T statin_0 0.89 0.004 C(0.2) T(0.8) CC 121 167 CT1048 1338 TT 2372 2671 (rs2304167) (0.82-0.96) statin_1 1.06 0.751C(0.19) T(0.81) CC 5 12 CT 40 73 TT 80 169 (0.73-1.54) 0.371584665hCV1202883 MTHFR G G_vs_A statin_0 1.08 0.038 A(0.3) G(0.7) AA 172 269AG 1695 1988 GG 1684 1934 (rs1801133) (1-1.17) statin_1 1.28 0.177A(0.32) G(0.68) AA 5 23 AG 57 117 GG 61 116 (0.9-1.82) 0.371786352hCV1376342 GP6 C C_vs_T statin_0 0.88 0.002 C(0.2) T(0.8) CC 115 159 CT1029 1342 TT 2386 2693 (rs1654416) (0.81-0.95) statin_1 1.05 0.809C(0.19) T(0.81) CC 5 14 CT 39 71 TT 79 172 (0.72-1.51) 0.406756226hCV11975250 F5 T T_vs_C statin_0 3.42 1E−51 C(0.97) T(0.03) CC 2934 3930CT 556 207 TT 23 7 (rs6025) (2.92-4.01) statin_1 4.78 2E−05 C(0.98)T(0.02) CC 99 239 CT 22 12 TT 2 0 (2.34-9.77) 0.407763342 hCV2103346DKFZP564J102 C C_vs_T statin_0 1.07 0.03 C(0.44) T(0.56) CC 753 862 CT1731 1988 TT 1029 1341 (rs11733307) (1.01-1.14) statin_1 1.22 0.201C(0.44) T(0.56) CC 28 52 CT 62 122 TT 31 85 (0.9-1.65) 0.410870664hCV15860324 PROCR C C_vs_T statin_0 1.33 4E−05 C(0.05) T(0.95) CC 17 13CT 431 298 TT 3073 3789 (rs2069946) (1.16-1.52) statin_1 1.03 0.928C(0.06) T(0.94) CC 1 2 CT 14 29 TT 107 226 (0.56-1.87) 0.412798308hCV11503469 FGG A A_vs_T statin_0 1.37 5E−19 A(0.27) T(0.73) AA 405 298AT 1544 1623 TT 1600 2265 (rs2066854) (1.28-1.47) statin_1 1.19 0.301A(0.3) T(0.7) AA 16 21 AT 52 111 TT 57 125 (0.86-1.64) 0.423539585hCV30562347 F11 G G_vs_A statin_0 1.28 0.003 A(0.04) G(0.96) AA 7 9 AG231 349 GG 3317 3824 (rs4253418) (1.09-1.51) statin_1 0.99 0.972 A(0.04)G(0.96) AA 2 2 AG 7 18 GG 114 237 (0.5-1.95) 0.435904222 hCV263841 NR1I2C C_vs_A statin_0 1.11 0.002 A(0.62) C(0.38) AA 1263 1578 AC 1667 2003CC 617 608 (rs1523127) (1.04-1.18) statin_1 0.97 0.85 A(0.62) C(0.38) AA46 97 AC 62 121 CC 16 38 (0.71-1.33) 0.43932399 hCV596331 F9 (rs6048) AA_vs_G statin_0 1.1 0.001 A(0.7) G(0.3) AA 2171 2457 AG 766 906 GG 583813 (1.04-1.17) statin_1 1.22 0.148 A(0.69) G(0.31) AA 83 161 AG 21 33GG 19 62 (0.93-1.61) 0.45280106 hCV8718961 RDH13 A A_vs_T statin_0 0.890.009 A(0.16) T(0.84) AA 68 104 AT 866 1114 TT 2591 2986 (rs1654451)(0.81-0.97) statin_1 1.04 0.853 A(0.15) T(0.85) AA 3 9 AT 33 62 TT 86188 (0.69-1.56) 0.469253388 hCV30710896 F2 T T_vs_C statin_0 1.28 0.012C(0.98) T(0.02) CC 3315 4011 CT 198 189 TT 7 4 (rs3136520) (1.06-1.56)statin_1 0.9 0.808 C(0.97) T(0.03) CC 114 244 CT 7 14 TT 0 1 (0.37-2.18)0.497858665 hCV8717873 GP6 A A_vs_G statin_0 1.17 2E−04 A(0.82) G(0.18)AA 2488 2783 AG 954 1265 GG 93 136 (rs1613662) (1.08-1.27) statin_1 1.020.922 A(0.82) G(0.18) AA 85 174 AG 34 73 GG 5 10 (0.69-1.5) 0.518388541hCV2892877 FGA C C_vs_T statin_0 1.38 4E-12 C(0.24) T(0.76) CC 14 18 CT1808 1810 TT 1485 2090 (rs6050) (1.26-1.52) statin_1 1.19 0.447 C(0.25)T(0.75) CC 1 0 CT 61 121 TT 52 117 (0.76-1.85) 0.525140093 hCV2499170(rs169713) C C_vs_T statin_0 1.1 0.015 C(0.2) T(0.8) CC 175 200 CT 11851305 TT 2135 2694 (1.02-1.19) statin_1 0.96 0.847 C(0.2) T(0.8) CC 3 5CT 41 92 TT 78 160 (0.64-1.44) 0.541874674 hCV11503414 FGG A A_vs_Gstatin_0 1.37 4E−19 A(0.26) G(0.74) AA 396 294 AG 1535 1623 GG 1584 2266(r52066865) (1.28-1.47) statin_1 1.23 0.219 A(0.29) G(0.71) AA 15 20 AG52 111 GG 54 126 (0.88-1.71) 0.546620019 hCV15949414 XYLB G G_vs_Astatin_0 1.34 2E−04 A(0.05) G(0.95) AA 13 14 AG 257 418 GG 3266 3762(rs2234628) (1.15-1.56) statin_1 1.07 0.862 A(0.04) G(0.96) AG 10 22 GG112 237 0 0 0 (0.49-2.36) 0.583697812 hCV25597241 AQP2 A A_vs_G statin_01.12 0.038 A(0.09) G(0.91) AA 33 32 AG 607 659 GG 2877 3513 (r53782320)(1.01-1.25) statin_1 0.96 0.895 A(0.09) G(0.91) AA 0 3 AG 21 40 GG 101216 (0.56-1.66) 0.619356604 hCV16177220 ODZ1 C C_vs_T statin_0 1.090.009 C(0.8) T(0.2) CC 2613 2982 CT 593 737 TT 347 475 (rs2266911)(1.02-1.17) statin_1 1 0.996 C(0.83) T(0.17) CT 23 34 TT 10 27 CC 92 195(0.72-1.39) 0.621640282 hCV27902808 CYP4V2 T T_vs_C statin_0 0.85 9E−07C(0.64) T(0.36) CC 1597 1711 CT 1557 1935 TT 364 555 (r54253236)(0.79-0.9) statin_1 0.92 0.587 C(0.61) T(0.39) CC 44 100 CT 65 114 TT 1345 (0.67-1.25) 0.652386012 hCV11541681 LOC200420 C C_vs_G statin_0 1.070.032 C(0.37) G(0.63) CC 560 583 CG 1631 1949 GG 1351 1661 (rs2001490)(1.01-1.14) statin_1 0.99 0.969 C(0.35) G(0.65) CC 15 28 CG 57 125 GG 52104 (0.72-1.38) 0.66407521 hDV71075942 (rs8176719) G G_vs_T statin_01.67 6E−51 G(0.34) T(0.66) GG 669 512 TG 1896 1840 TT 951 1849(1.56-1.79) statin_1 1.81 6E−04 G(0.35) T(0.65) GG 18 31 TG 80 120 TT 24108 (1.29-2.54) 0.676672364 hCV30690780 AKT3 C C_vs_A statin_0 1.152E−04 A(0.77) C(0.23) AA 2011 2515 AC 1236 1466 CC 268 212 (rs10737888)(1.07-1.24) statin_1 1.07 0.702 A(0.76) C(0.24) AA 70 151 AC 42 91 CC 1017 (0.76-1.51) 0.701926538 hCV1825046 PROCR C C_vs_T statin_0 0.84 7E−08C(0.41) T(0.59) CC 494 706 CT 1572 2005 TT 1457 1494 (rs2069952)(0.78-0.89) statin_1 0.79 0.145 C(0.4) T(0.6) CC 15 38 CT 53 130 TT 5391 (0.57-1.09) 0.713175712 hCV31523608 AKT3 G G_vs_A statin_0 1.13 4E−04A(0.67) G(0.33) AA 1482 1917 AG 1578 1823 GG 460 464 (rs12744297)(1.06-1.21) statin_1 1.2 0.287 A(0.66) G(0.34) AA 45 110 AG 62 123 GG 1526 (0.86-1.66) 0.715483519 hCV15990789 OTOG G G_vs_A statin_0 1.07 0.045A(0.41) G(0.59) AA 544 690 AG 1643 2001 GG 1320 1478 (rs2355466)(1-1.14) statin_1 0.99 0.975 A(0.36) G(0.64) AA 15 33 AG 58 117 GG 48101 (0.72-1.38) 0.737326509 hCV30690777 AKT3 A A_vs_G statin_0 1.140.004 A(0.14) G(0.86) AA 99 75 AG 911 1035 GG 2505 3085 (rs12045585)(1.04-1.24) statin_1 1.07 0.747 A(0.16) G(0.84) AA 5 7 AG 32 70 GG 85180 (0.71-1.6) 0.738278618 hCV15860433 (rs2070006) T T_vs_C statin_01.24 1E−10 C(0.61) T(0.39) CC 1090 1550 CT 1748 1971 TT 713 669(1.16-1.32) statin_1 1.3 0.091 C(0.6) T(0.4) CC 37 96 CT 60 119 TT 28 43(0.96-1.75) 0.798652766 hCV25748719 NAP5 ( ) C C_vs_T statin_0 1.080.036 C(0.77) T(0.23) CC 2163 2462 CT 1206 1490 TT 169 225 (1.01-1.17)statin_1 1.15 0.482 C(0.77) T(0.23) CC 74 152 CT 50 91 TT 1 13(0.78-1.68) 0.804517403 hCV2986566 F9 A A_vs_T statin_0 1.15 0.015A(0.06) T(0.94) AA 113 106 AT 258 268 TT 3152 3826 (rs4149755)(1.03-1.28) statin_1 1.07 0.783 A(0.06) T(0.94) AA 5 9 AT 5 11 TT 111239 (0.65-1.78) 0.808271852 hCV32291301 KLKB1 A A_vs_G statin_0 1.26E−05 A(0.84) G(0.16) AA 2649 2949 AG 835 1140 GG 79 114 (rs4253302)(1.1-1.31) statin_1 1.25 0.282 A(0.82) G(0.18) AA 93 178 AG 28 70 GG 411 (0.83-1.87) 0.841280102 hCV1841973 (rs1799808) T T_vs_C statin_0 0.940.049 C(0.65) T(0.35) CC 1545 1756 CT 1565 1918 TT 405 525 (0.88-1)statin_1 0.9 0.515 C(0.64) T(0.36) CC 57 111 CT 48 105 TT 17 40(0.67-1.23) 0.86593208 hCV25990131 CYP4V2 A A_vs_C statin_0 1.2 2E−07A(0.64) C(0.36) AA 1584 1665 AC 1430 1808 CC 351 527 (rs13146272)(1.12-1.28) statin_1 1.16 0.358 A(0.62) C(0.38) AA 51 97 AC 56 107 CC 1338 (0.84-1.6) 0.87763198 hCV25620145 PROCR G G_vs_A statin_0 1.18 5E−04A(0.88) G(0.12) AA 2601 3203 AG 869 917 GG 74 62 (rs867186) (1.07-1.29)statin_1 1.14 0.565 A(0.87) G(0.13) AA 91 194 AG 30 61 GG 3 3(0.73-1.77) 0.918870113 hCV1841974 (rs1799809) G G_vs_A statin_0 1.153E−05 A(0.57) G(0.43) AA 1007 1362 AG 1741 2046 GG 770 794 (1.08-1.22)statin_1 1.17 0.298 A(0.56) G(0.44) AA 38 82 AG 50 122 GG 34 53(0.87-1.57) 0.927314636 hCV233148 AKT3 C C_vs_G statin_0 1.15 6E−05C(0.28) G(0.72) CC 378 318 CG 1434 1694 GG 1735 2171 (rs1417121)(1.08-1.23) statin_1 1.14 0.44 C(0.27) G(0.73) CC 11 21 CG 52 98 GG 61138 (0.82-1.59) 0.928029357 hCV1841983 PROC C C_vs_T statin_0 1.13 3E−04C(0.34) T(0.66) CC 501 504 CT 1610 1873 TT 1392 1808 (rs5937)(1.06-1.21) statin_1 1.12 0.484 C(0.36) T(0.64) CC 22 34 CT 49 117 TT 50107 (0.82-1.52) 0.96355332 hCV30747430 NR1I2 T T_vs_C statin_0 1.148E−04 C(0.82) T(0.18) CC 2251 2803 CT 1095 1253 TT 179 148 (rs11712211)(1.06-1.24) statin_1 1.15 0.484 C(0.83) T(0.17) CC 80 177 CT 36 74 TT 68 (0.78-1.69) 0.970695776 hCV18141975 PROC T T_vs_A statin_0 1.13 1E−04A(0.57) T(0.43) AA 1036 1374 AT 1748 2035 TT 765 789 (rs1799810)(1.06-1.21) statin_1 1.13 0.403 A(0.56) T(0.44) AA 40 82 AT 49 122 TT 3453 (0.85-1.52) Allele1 Allele2 Geno- Geno- Geno- additive Pint markerGene Risk (allele (allele type Control type Control type Controlstatin*SNP (hCV #) (SNP rs #) Allele parameter Strata OR (95% Cl)P-value freq) freq) 1 Case 1 1 2 Case 2 2 3 Case 3 3 0.002528557hCV2211618 DDT G G_vs_C statin_0 1.08 0.015 C(0.57) G(0.43) CC 1088 1358CG 1710 2002 GG 710 750 (rs12483950) (1.02-1.15) statin_1 0.66 0.011C(0.53) G(0.47) CC 46 74 CG 66 118 GG 13 58 (0.48-0.91) SNPs are rankedabove in Table 5 by P(int) statin*SNP from the additive model. p(int)statin*SNP: P value <0.05 (Wald test) for statin*SNP interaction term(ModelFormula: VTE~SNP + statin user or nonuser + SNP*statin + age +sex) from an additive model. Endpoint: VT (including DVT and PE) Strata:statin_0 (statin nonusers), statin_1 (statin users) Model: additive

TABLE 6 Association of statin use and VTE in SNP genotype subgroups inMEGA, and VTE risk of that genotype in statin nonusers in MEGA (last 2columns) Model: SNP~ Model: VTE~statin + age + sex VTE + age OR ref- OR(95% Cl) erence statin (95% for P(int group for statin non- statinstatin Cl for P for Risk statin* statin*S P(int users, users usersnonusers VTE VTE Gene (rs #) Allele Strata model VTE P NP) statin*SNP)cases cases controls controls risk risk DDT G GG 0.24 6E−06 0.001202GGvs.CC 13 710 58 750 1.18 0.0134 (rs12483950) (0.13- (0.1) (0.2) (0.23)(0.18) (1.03- 0.44) 1.34) DDT G GC 0.67 0.013 0.494961 GCvs.CC  66 1710118 2002 1.07 0.2276 (rs12483950) (0.49- (0.53) (0.49) (0.47) (0.49)(0.96- 0.92) 1.18) DDT G CC 0.78 0.196 0.002529  46 1088 74 1358 1.080.0148 (rs12483950) (0.53- (0.37) (0.31) (0.3) (0.33) (1.02- 1.14) 1.15)DDT G GC + rec 0.71 0.006 0.001199 GGvs.GC +  13 710 58 750 1.13 0.0309(rs12483950) CC (0.56- CC (1.01- 0.91) 1.27) DDT G GC + dom 0.52 4E−060.077571 GC +  79 2420 176 2752 1.1 0.0633 (rs12483950) GG (0.4- GGvs.CC(0.99- 0.69) 1.21) DDT G add 0.002529 1.08 0.0148 (rs12483950) (1.02-1.15) F2RL1 T TT 0.47 7E−04 0.067 TTvs.CC  31 1095 77 1248 1.08 0.233(rs1529505) (0.31- (0.25) (0.31) (0.3) (0.3) (0.95- 0.73) 1.23) F2RL1 TTC 0.55 2E−04 0.163 TCvs.CC  62 1722 131 2025 1.05 0.457 (rs1529505)(0.4- (0.5) (0.49) (0.51) (0.49) (0.93- 0.75) 1.18) F2RL1 T CC 0.880.595  32 709 48 872 ref ref (rs1529505) (0.55- (0.26) (0.2) (0.19)(0.21) 1.41) F2RL1) T TT rec 0.63 5E−04 0.220 TTvs.TT  31 1095 77 12481.05 0.350 (rs1529505 (0.49- (0.95- 0.82) 1.15) F2RL1 T TC + dom 0.52(0.4- 4E−07 0.083 TC +  93 2817 208 3273 1.06 0.310 (rs1529505) TT 0.67)TTvs.CC (0.95- 1.18) LOC729672 T TT 0.62 0.168 0.199 TTvs.CC  15 332 22355 1.11 0.193 (rs4334028) (0.31- (0.12) (0.09) (0.08) (0.08) (0.95-1.23) 1.31) LOC729672 T TC 0.69 0.023 0.082 TCvs.CC  63 1521 113 18240.99 0.889 (rs4334028) (0.5- (0.51) (0.43) (0.44) (0.43) (0.9- 0.95)1.09) LOC729672 T CC 0.46 1E−05  46 1705 124 2030 ref ref (rs4334028)(0.32- (0.37) (0.48) (0.48) (0.48) 0.65) LOC729672 T TT rec 0.57 2E−060.446 TTvs.TT  15 332 22 355 1.12 0.164 (rs4334028) (0.45- (0.96- 0.72)1.31) LOC729672 T TC + dom 0.68 0.009 0.060 TC +  78 1853 135 2179 1.010.777 (rs4334028) TT (0.51- TTvs.CC (0.93- 0.91) 1.11) ASAH1 T TT 0.850.487 0.085 TTvs.CC  32 791 50 1032 0.85 0.013 (rs12544854) (0.54-(0.2645) (0.2264) (0.1946) (0.2455) (0.75- 1.35) 0.97) ASAH1 T TC 0.531E−04 0.833 TCvs.CC  57 1707 134 2065 0.92 0.113 (rs12544854) (0.38-(0.4711) (0.4886) (0.5214) (0.4913) (0.82- 0.73) 1.02) ASAH1 T CC 0.50.002 32 996 73 1106 ref ref (rs12544854) (9.32- (0.2645) (0.2851)(0.284) (0.2631) 0.77) ASAH1 T TT rec 0.52 6E−07 0.055 TTvs.TT  32 79150 1032 0.9 0.054 (rs12544854) (0.4- (0.81-1) 0.67) ASAH1 T TC + dom0.61 3E−04 0.404 TC +  89 2498 184 3097 0.9 0.032 (rs12544854) TT (0.47-TTvs.CC (0.81- 0.8) 0.99) LOC730144 T TC 1 0.995 0.051 TCvs.TT  23 43135 616 0.59 0.080 (rs4262503) (0.58- (0.19) (0.12) (0.14) (0.15) (0.33-1.73) 1.06) LOC730144 T TT 0.52 2E−07 101 3105 224 3561 ref ref(rs4262503) (0.41- (0.81) (0.87) (0.86) (0.85) 0.66) LOC730144 T TT rec0.98 0.954 0.060 TCvs.TT 101 3105 224 3561 1.22 0.003 (rs4262503) (0.57-(1.07- 1.7) 1.39) LOC730144 T TC + dom 0.57 1E−06 n/a (rs4262503) TT(0.46- 0.72) SNPs in Table 6 had additive P interaction <0.1 in MEGA.P(int) = P interaction from the Wald test for statin*SNP from thefollowing model: VTE~SNP + statin user or nonuser + SNP*statin user ornonuser + age + sex. OR (95% Cl) and P value for VTE~SNP in last 2columns calculated in statin nonusers. VT is interchangeably referred toas VTE.

TABLE 7 Statin response by genotype group Risk of VT in no HR HR statinuse group 95% 95% EVE- Cl Cl GE- NTS_ TO- EVE- lo- up- P- P NO_ PLA-TAL_ GENO_ STATIN_ NTS_ TOTAL HR_ wer_ per_ value_ (INT)_ PLA- CE- PLA-SNP MODE RESP USE RESP RESP RESP RESP RESP RESP RESP CEBO BO CEBOhCV7543812 GEN TT statin 40 51 1.04 0.631 1.7243 0.8698 0.00045 TT 136195 hCV7543812 GEN TT no statin 136 195 ref . . . 0.00045 . . hCV7543812GEN TC statin 65 134 0.56 0.389 0.7992 0.0015 0.00045 TC 276 283hCV7543812 GEN TC no statin 276 283 ref . . . 0.00045 . . hCV7543812 GENCC statin 20 72 0.28 0.156 0.5093 <.0001 0.00045 CC 126 129 hCV7543812GEN CC no statin 126 129 ref . . . 0.00045 . . hCV7543812 REC TC +statin 85 206 0.46 0.337 0.6217 <.0001 0.00046 TT 136 195 hCV7543812 RECTC + no statin 402 412 ref . . . 0.00046 . . CC hCV2690378 GEN GG statin51 71 0.82 0.53 1.2743 0.3805 0.00439 GG 187 203 hCV2690378 GEN GG nostatin 187 203 ref . . . 0.00439 . . hCV2690378 GEN GT statin 47 14 00.37 0.248 0.5445 <.0001 0.00439 GT 272 287 hCV2690378 GEN GT no statin272 287 ref . . . 0.00439 . . hCV2690378 GEN TT statin 27 46 0.89 0.4941.6077 0.7017 0.00439 TT 79 117 hCV2690378 GEN TT no statin 79 117 ref .. . 0.00439 . . hCV7543812 DOM TC + statin 105 185 0.69 0.519 0.92870.014 0.0048 TC + 412 478 TT TT hCV7543812 DOM TC + no statin 412 478ref . . . 0.0048 . . TT hCV931685 GEN GG statin 90 205 0.48 0.356 0.6484<.0001 0.00984 GG 413 431 hCV931685 GEN GG no statin 413 431 ref . . .0.00984 . . hCV931685 GEN GT statin 29 48 0.86 0.492 1.5118 0.60560.00984 GT 120 161 hCV931685 GEN GT no statin 120 161 ref . . . 0.00984. . hCV931685 GEN TT statin 6 4 2.76 0.489 15.611 0.25 0.00984 TT 6 15hCV931685 GEN TT no statin 6 15 ref . . . 0.00984 . . hCV11686277 GEN CCstatin 51 70 0.82 0.531 1.2762 0.3845 0.01246 CC 190 207 hCV11686277 GENCC no statin 190 207 ref . . . 0.01246 . . hCV11686277 GEN CG statin 48140 0.39 0.264 0.5766 <.0001 0.01246 CG 271 292 hCV11686277 GEN CG nostatin 271 292 ref . . . 0.01246 . . hCV11686277 GEN GG statin 26 470.77 0.426 1.4035 0.3976 0.01246 GG 78 108 hCV11686277 GEN GG no statin78 108 ref . . . 0.01246 . . hCV29260019 REC GA + statin 81 138 0.770.553 1.0792 0.1302 0.01356 GG 219 229 AA hCV29260019 REC GA + no statin319 378 ref . . . 0.01356 . . AA hDV70820190 DOM GA + statin 116 2520.54 0.416 0.7072 <.0001 0.01407 GA + 525 584 GG GG hDV70820190 DOM GA +no statin 525 584 ref . . . 0.01407 . . GG hCV931685 REC GT + statin 3552 0.98 0.579 1.6589 0.9396 0.01448 GG 413 431 TT hCV931685 REC GT + nostatin 126 176 ref . . . 0.01448 . . TT hDV70437895 DOM CT + statin 108237 0.52 0.397 0.6865 <.0001 0.01491 CT + 505 550 CC CC hDV70437895 DOMCT + no statin 505 550 ref . . . 0.01491 . . . CC hCV931685 DOM GT +statin 119 253 0.55 0.422 0.7148 <.0001 0.01611 GT + 533 592 GG GGhCV931685 DOM GT + no statin 533 592 ref . . . 0.01611 . . GGhCV29245634 GEN CC statin 104 227 0.5 0.38 0.6657 <.0001 0.01659 CC 471509 hCV29245634 GEN CC no statin 471 509 ref . . . 0.01659 . .hCV29245634 GEN CT statin 21 28 1.45 0.707 2.9636 0.3114 0.01659 CT 6496 hCV29245634 GEN CT no statin 64 96 ref . . . 0.01659 . . hCV29245634GEN TT statin 0 2 0 0 2E + 0.9403 0.01659 TT 4 1 hCV29245634 GEN TT nostatin 4 1 ref . . . 0.01659 . . hDV70437895 GEN CC statin 65 148 0.490.346 0.7051 0.0001 0.01843 CC 293 285 hDV70437895 GEN CC no statin 293285 ref . . . 0.01843 . . hDV70437895 GEN CT statin 43 89 0.56 0.3640.8634 0.0086 0.01843 CT 212 265 hDV70437895 GEN CT no statin 212 265ref . . . 0.01843 . . hDV70437895 GEN TT statin 17 20 1.48 0.602 3.63040.3932 0.01843 TT 34 57 hDV70437895 GEN TT no statin 34 57 ref . . .0.01843 . . hDV72050312 REC GA+ statin 63 98 0.83 0.562 1.2327 0.35930.01937 GG 337 368 AA hDV72050312 REC GA + no statin 201 239 ref . . .0.01937 . . AA hCV29948033 DOM TC + statin 116 251 0.53 0.409 0.6979<.0001 0.02073 TC + 511 572 TT TT hCV29948033 DOM TC + no statin 511 572ref . . . 0.02073 . . TT hDV70794769 REC CT + statin 63 99 0.83 0.5621.2319 0.358 0.02149 CC 334 364 TT hDV70794769 REC CT + no statin 204243 ref . . . 0.02149 . . TT hCV12066124 REC CT + statin 95 189 0.660.485 0.896 0.0078 0.02348 CC 193 169 TT hCV12066124 REC CT + no statin341 435 ref . . . 0.02348 . . TT hCV3054799 REC AG + statin 83 132 0.70.503 0.9774 0.0362 0.02372 AA 211 247 GG hCV3054799 REC AG + no statin328 360 ref . . . 0.02372 . . GG hDV70820190 GEN GG statin 79 178 0.490.354 0.6732 <.0001 0.02944 GG 367 389 hDV70820190 GEN GG no statin 367389 ref . . . 0.02944 . . hDV70820190 GEN GA statin 37 74 0.68 0.4211.0862 0.1057 0.02944 GA 158 195 hDV70820190 GEN GA no statin 158 195ref . . . 0.02944 . . hDV70820190 GEN AA statin 8 5 2.05 0.506 8.30680.3149 0.02944 AA 14 23 hDV70820190 GEN AA no statin 14 23 ref . . .0.02944 . . hCV1396435 REC GT + statin 95 172 0.68 0.501 0.9275 0.01470.02966 GG 187 191 TT hCV1396435 REC GT + no statin 351 416 ref . . .0.02966 . . TT hDV70437895 REC CT + statin 60 109 0.68 0.461 0.98860.0435 0.03119 CC 293 285 TT hDV70437895 REC CT + no statin 246 322 ref. . . 0.03119 . . TT hCV11686277 REC CG + statin 74 187 0.47 0.3420.6558 <.0001 0.03337 CC 190 207 GG hCV11686277 REC CG + no statin 349400 ref . . . 0.03337 . . GG hCV11778561 DOM AT + statin 92 210 0.490.369 0.6625 <.0001 0.03501 AT + 458 501 AA AA hCV11778561 DOM AT + nostatin 458 501 ref . . . 0.03501 . . AA hCV2690378 REC GT + statin 74186 0.47 0.343 0.6562 <.0001 0.04169 GG 187 203 TT hCV2690378 REC GT +no statin 351 404 ref . . . 0.04169 . . TT hDV70830411 REC TG + statin77 179 0.47 0.339 0.6482 <.0001 0.04469 TT 186 231 GG hDV70830411 RECTG + no statin 353 376 ref . . . 0.04469 . . GG hCV7422169 DOM GA +statin 118 253 0.54 0.417 0.708 <.0001 0.04504 GA + 515 581 GG GGhCV7422169 DOM GA + no statin 515 581 ref . . . 0.04504 . . GGhCV29260019 GEN GG statin 42 119 0.36 0.234 0.5439 <.0001 0.04625 GG 219229 hCV29260019 GEN GG no statin 219 229 ref . . . 0.04625 . .hCV29260019 GEN GA statin 65 106 0.75 0.513 1.0947 0.1357 0.04625 GA 254292 hCV29260019 GEN GA no statin 254 292 ref . . . 0.04625 . .hCV29260019 GEN GA statin 16 32 0.86 0.419 1.7833 0.6933 0.04625 AA 6586 hCV29260019 GEN GA no statin 65 86 ref . . . 0.04625 . . hCV29245634REC CT + statin 21 30 1.32 0.651 2.6788 0.4409 0.04661 CC 471 509 TThCV29245634 REC CT + no statin 68 97 ref . . . 0.04661 . . TThCV29948033 GEN TT statin 66 153 0.5 0.353 0.7033 <.0001 0.05902 TT 338383 hCV29948033 GEN TT no statin 338 383 ref . . . 0.05902 . .hCV29948033 GEN TC statin 50 98 0.58 0.382 0.8933 0.0131 0.05902 TC 173189 hCV29948033 GEN TC no statin 173 189 ref . . . 0.05902 . .hCV29948033 GEN CC statin 9 6 2.72 0.715 10.345 0.1423 0.05902 CC 27 34hCV29948033 GEN CC no statin 27 34 ref . . . 0.05902 . . hCV3054799 GENAA statin 41 125 0.42 0.273 0.6386 <.0001 0.06051 AA 211 247 hCV3054799GEN AA no statin 211 247 ref . . . 0.06051 . . hCV3054799 GEN AG statin66 95 0.74 0.509 1.0894 0.1288 0.06051 AG 255 272 hCV3054799 GEN AG nostatin 255 272 ref . . . 0.06051 . . hCV3054799 GEN GG statin 17 37 0.570.284 1.1433 0.1135 0.06051 GG 73 88 hCV3054799 GEN GG no statin 73 88ref . . . 0.06051 . . hCV31671070 DOM AG + statin 125 251 0.59 0.4510.7603 <.0001 0.07368 AG + 528 591 AA AA hCV31671070 DOM AG + no statin528 591 ref . . . 0.07368 . . AA hCV12066124 GEN CC statin 27 68 0.380.225 0.625 0.0002 0.07542 CC 193 169 hCV12066124 GEN CC no statin 193169 ref . . . 0.07542 . . hCV12066124 GEN CT statin 72 129 0.68 0.4750.9711 0.0339 0.07542 CT 254 296 hCV12066124 GEN CT no statin 254 296ref . . . 0.07542 . . hCV12066124 GEN TT statin 23 60 0.6 0.328 1.10420.101 0.07542 TT 87 139 hCV12066124 GEN TT no statin 87 139 ref . . .0.07542 . . hCV1772768 REC GA + statin 84 146 0.64 0.463 0.8972 0.00930.0798 GG 230 256 AA hCV1772768 REC GA + no statin 308 351 ref . . .0.0798 . . AA hDV72050312 GEN GG statin 62 159 0.43 0.305 0.6143 <.00010.08047 GG 337 368 hDV72050312 GEN GG no statin 337 368 ref . . .0.08047 . . hDV72050312 GEN GA statin 50 83 0.81 0.528 1.2483 0.34240.08047 GA 172 215 hDV72050312 GEN GA no statin 172 215 ref . . .0.08047 . . hDV72050312 GEN AA statin 13 15 0.79 0.285 2.1974 0.65280.08047 AA 29 24 hDV72050312 GEN AA no statin 29 24 ref . . . 0.08047 .. hCV9540478 REC TC + statin 38 94 0.44 0.282 0.6919 0.0004 0.08096 TT335 402 CC hCV9540478 REC TC + no statin 201 204 ref . . . 0.08096 . .CC hCV9540478 DOM GT + statin 98 211 0.52 0.389 0.6943 <.0001 0.08114GT + 459 490 GG GG hCV9540478 DOM GT + no statin 459 490 ref . . .0.08114 . . GG hCV29245634 DOM CT + statin 125 255 0.58 0.446 0.7496<.0001 0.08203 CT + 535 605 CC CC hCV29245634 DOM CT + no statin 535 605ref . . . 0.08203 . . CC hCV16233239 REC AG + statin 48 86 0.8 0.5221.2301 0.3111 0.0829 AA 342 356 GG hCV16233239 REC AG + no statin 196251 ref . . . 0.0829 . . GG hCV3286482 DOM TC + statin 116 245 0.550.419 0.7162 <.0001 0.08603 TC + 517 572 TT TT hCV3286482 DOM TC + nostatin 517 572 ref . . . 0.8603 . . TT hDV70794769 GEN CC statin 62 1580.43 0.306 0.6163 <.0001 0.0899 CC 334 364 hDV70794769 GEN CC no statin334 364 ref . . . 0.0899 . . hDV70794769 GEN CT statin 50 84 0.82 0.5341.2614 0.3676 0.0899 CT 174 220 hDV70794769 GEN CT no statin 174 220 ref. . . 0.0899 . . hDV70794769 GEN TT statin 13 15 0.69 0.246 1.93960.4823 0.0899 TT 30 23 hDV70794769 GEN TT no statin 30 23 ref . . .0.0899 . . hDV77026147 DOM CT + statin 124 257 0.56 0.435 0.7324 <.00010.09216 CT + 535 602 CC CC hDV77026147 DOM CT + no statin 535 602 ref .. . 0.09216 . . CC hCV1396435 GEN GG statin 30 85 0.38 0.235 0.6270.0001 0.09466 GG 187 191 hCV1396435 GEN GG no statin 187 191 ref . . .0.09466 . . hCV1396435 GEN GT statin 75 134 0.67 0.473 0.9506 0.02480.09466 GT 258 305 hCV1396435 GEN GT no statin 258 305 ref . . . 0.09466. . hCV1396435 GEN TT statin 20 38 0.75 0.386 1.4425 0.384 0.09466 TT 93111 hCV1396435 GEN TT no statin 93 111 ref . . . 0.09466 . . hDV70820190REC GA + statin 45 79 0.77 0.491 1.1912 0.2358 0.09992 GG 367 389 AAhDV70820190 REC GA + no statin 172 218 ref . . . 0.09992 . . AA Statinresponse by genotype group Risk of VT in no statin use group HR HR HR HR95% 95% 95% 95% Cl Cl P- P_ Cl Cl HR_ lower upper_ value DF2_ GE- EVE-TO- lo- up- P- P_ PLA- PLA- PLA- PLA- PLA- NO_ NTS_ TAL HR_ wer_ per-value_ DF2_ SNP CEBO CEBO CEBO CEBO CEBO statin statin statin statinstatin statin statin statin hCV7543812 0.71 0.5117 0.989 0.043 0.0373 TT40 51 2.85 1.4892 5.4472 0.0016 0.0065 hCV7543812 . . . . . . . . . . .. hCV7543812 1 0.7414 1.343 0.9893 0.0373 TC 65 134 1.76 0.9862 3.14630.0557 0.0065 hCV7543812 . . . . . . . . . . . . hCV7543812 ref . . .0.0373 CC 20 72 ref . . . 0.0065 hCV7543812 . . . . . . . . . . . .hCV7543812 0.71 0.5499 0.923 0.0103 . TT 40 51 1.9 1.1708 3.0924 0.0094. hCV7543812 . . . . . . . . . . . . hCV2690378 1.35 0.9508 1.91 0.09360.133 GG 51 71 1.22 0.6713 2.2133 0.5154 0.0078 hCV2690378 . . . . . . .. . . . . hCV2690378 1.39 1.0016 1.941 0.0489 0.133 GT 47 140 0.570.3215 1.0235 0.0599 0.0078 hCV2690378 . . . . . . . . . . . .hCV2690378 ref . . . 0.133 TT 27 46 ref . . . 0.0078 hCV2690378 . . . .. . . . . . . hCV7543812 0.88 0.666 1.165 0.3726 . TC + 105 185 2.061.1851 3.5833 0.0104 . TT hCV7543812 . . . . . . . . . . . . hCV9316852.26 0.8633 5.895 0.0969 0.0639 GG 90 205 0.3 0.0821 1.0866 0.0667 0.104hCV931685 . . . . . . . . . . . . hCV931685 1.76 0.6621 4.696 0.25640.0639 GT 29 48 0.42 0.1077 1.6061 0.2031 0.104 hCV931685 . . . . . . .. . . . . hCV931685 ref . . . 0.0639 TT 6 4 ref . . . 0.104 hCV931685 .. . . . . . . . . . . hCV11686277 1.25 0.8787 1.779 0.2145 0.357 CC 5170 1.31 0.7207 2.3934 0.3734 0.0098 hCV11686277 . . . . . . . . . . . .hCV11686277 1.27 0.9077 1.776 0.1632 0.357 CG 48 140 0.62 0.3476 1.11120.1086 0.0098 hCV11686277 . . . . . . . . . . . . hCV11686277 ref . . .0.357 GG 26 47 ref . . . 0.0098 hCV11686277 . . . . . . . . . . . .hCV29260019 1.14 0.8974 1.446 0.2846 . GG 42 119 0.6 0.3805 0.93130.0231 . hCV29260019 . . . . . . . . . . . . hDV70820190 1.43 0.72882.82 0.2967 . GA + 116 252 0.29 0.0922 0.903 0.0327 . GG hDV70820190 . .. . . . . . . . . . hCV931685 1.33 1.0163 1.731 0.0376 . GG 90 205 0.650.3932 1.0614 0.0846 . hCV931685 . . . . . . . . . . . . hDV704378951.53 0.9848 2.388 0.0585 . CT + 108 237 0.53 0.2635 1.0523 0.0694 . CChDV70437895 . . . . . . . . . . . hCV931685 2.12 0.8129 5.524 0.1245 .GT + 119 253 0.32 0.0884 1.1575 0.0824 . GG hCV931685 . . . . . . . . .. . hCV29245634 0.26 0.0288 2.338 0.2291 0.066 CC 104 227 43000 0 1E+0.9592 0.2804 182 hCV29245634 . . . . . . . . . hCV29245634 0.18 0.02011.691 0.1347 0.066 CT 21 28 7100 0 2E+182 0.9573 0.2804 hCV29245634 . .. . . . . . . . . . hCV29245634 ref . . . 0.066 TT 0 2 ref . . . 0.2804hCV29245634 . . . . . . . . . . . . hDV70437895 1.71 1.086 2.706 0.02060.0234 CC 65 148 0.51 0.25 1.0405 0.0642 0.1798 hDV70437895 . . . . . .. . . . . . hDV70437895 1.34 0.8434 2.128 0.2155 0.0234 CT 43 89 0.560.2621 1.1868 0.1297 0.1798 hDV70437895 . . . . . . . . . . . .hDV70437895 ref . . . 0.0234 TT 17 20 ref . . . 0.1798 hDV70437895 . . .. . . . . . . . . hDV72050312 1.1 0.8637 1.394 0.4473 . GG 62 159 0.610.3943 0.9355 0.0237 . hDV72050312 . . . . . . . . . . . . hCV299480331.16 0.6865 1.945 0.5864 . TC + 116 251 0.3 0.1035 0.8704 0.0267 . TThCV29948033 . . . . . . . . . . . . hDV70794769 1.1 0.8686 1.4 0.422 .CC 62 158 0.62 0.4006 0.9498 0.0282 . hDV70794769 . . . . . . . . . . .. hCV12066124 1.49 1.1552 1.911 0.002 . CC 27 68 0.77 0.4624 1.29 0.3237. hCV12066124 . . . . . . . . . . . . hCV3054799 0.94 0.7447 1.1980.6363 . AA 41 125 0.52 0.3344 0.8198 0.0047 . hCV3054799 . . . . . . .. . . . . hDV70820190 1.5 0.7614 2.974 0.2398 0.2887 GG 79 178 0.280.088 0.8787 0.0292 0.0908 hDV70820190 . . . . . . . . . . . .hDV70820190 1.29 0.642 2.597 0.4736 0.2887 GA 37 74 0.31 0.0957 1.02680.0553 0.0908 hDV70820190 . . . . . . . . . . . . hDV70820190 ref . . .0.2887 AA 8 5 ref . . . 0.0908 hDV70820190 . . . . . . . . . . . .hCV1396435 1.16 0.905 1.485 0.242 . GG 30 85 0.63 0.3882 1.0284 0.0647 .hCV1396435 . . . . . . . . . . . . hDV70437895 1.34 1.0607 1.691 0.0141. CC 65 148 0.79 0.5162 1.2238 0.297 . hDV70437895 . . . . . . . . . . .. hCV11686277 1.04 0.8177 1.333 0.7295 . CC 51 70 1.83 1.1658 2.87510.0086 . hCV11686277 . . . . . . . . . . . . hCV11778561 1.22 0.88841.675 0.2194 . AT + 92 210 0.61 0.3675 1.0239 0.0615 . AA hCV11778561 .. . . . . . . . . . . hCV2690378 1.05 0.8232 1.345 0.6842 . GG 51 711.79 1.1434 2.8144 0.011 . hCV2690378 . . . . . . . . . . . .hDV70830411 0.85 0.6685 1.085 0.1942 . TT 48 77 1.45 0.9242 2.26910.1061 . hDV70830411 . . . . . . . . . . . . hCV7422169 0.99 0.56171.754 0.9792 . GA + 118 253 0.26 0.0748 0.9243 0.0373 . GG hCV7422169 .. . . . . . . . . . . hCV29260019 1.28 0.8796 1.853 0.1987 0.416 GG 42119 0.71 0.3538 1.4308 0.3395 0.0605 hCV29260019 . . . . . . . . . . . .hCV29260019 1.16 0.8036 1.665 0.4335 0.416 GA 65 106 1.26 0.6363 2.47660.5118 0.0605 hCV29260019 . . . . . . . . . . . . hCV29260019 ref . . .0.416 AA 16 32 ref . . . 0.0605 hCV29260019 . . . . . . . . . . . .hCV29245634 1.34 0.9614 1.881 0.0836 . CC 104 227 0.65 0.3571 1.19680.1683 . hCV29245634 . . . . . . . . . . . . hCV29948033 1.14 0.67251.931 0.6271 0.8191 TT 66 153 0.28 0.0951 0.8275 0.0213 0.0674hCV29948033 . . . . . . . . . . . . hCV29948033 1.19 0.6871 2.054 0.53740.8191 TC 50 98 0.33 0.1102 0.9849 0.0469 0.0674 hCV29948033 . . . . . .. . . . . . hCV29948033 ref . . . 0.8191 CC 9 6 ref . . . 0.0674hCV29948033 . . . . . . . . . . . . hCV3054799 1.04 0.7272 1.499 0.81570.6888 AA 41 125 0.72 0.3683 1.4234 0.3491 0.0078 hCV3054799 . . . . . .. . . . . . hCV3054799 1.14 0.7991 1.626 0.4703 0.6888 AG 66 95 1.540.7943 2.9729 0.202 0.0078 hCV3054799 . . . . . . . . . . . . hCV3054799ref . . . 0.6888 GG 17 37 ref . . . 0.0078 hCV3054799 . . . . . . . . .. . . hCV31671070 1.43 0.6402 3.173 0.3855 . AG + 125 251 2E + 0 .0.9868 . AA hCV31671070 . . . . . . . . . . . . hCV12066124 1.87 1.33462.634 0.0003 0.0012 CC 27 68 1.01 0.5219 1.9537 0.977 0.2627 hCV12066124. . . . . . . . . . . . hCV12066124 1.38 1.0085 1.901 0.0442 0.0012 CT72 129 1.45 0.8244 2.5485 0.1973 0.2627 hCV12066124 . . . . . . . . . .. . hCV12066124 ref . . . 0.0012 TT 23 60 ref . . . 0.2627 hCV12066124 .. . . . . . . . . . hCV1772768 1.03 0.8109 1.298 0.8305 . GG 41 110 0.650.4134 1.0147 0.0579 hCV1772768 . . . . . . . . . . . . hDV72050312 0.790.4485 1.382 0.405 0.3308 GG 62 159 0.45 0.2043 1.0116 0.0534 0.054hDV72050312 . . . . . . . . . . . . hDV72050312 0.69 0.3843 1.223 0.20110.3308 GA 50 83 0.7 0.3087 1.6002 0.4009 0.054 hDV72050312 . . . . . . .. . . . hDV72050312 ref . . . 0.3308 AA 13 15 ref . . . 0.054hDV72050312 . . . . . . . . . . . . hCV9540478 0.84 0.6583 1.072 0.1604. TT 87 163 1.33 0.8381 2.0967 0.2282 . hCV9540478 . . . . . . . . . . .. hCV9540478 1.37 1.0052 1.881 0.0463 . GT + 98 211 0.79 0.4646 1.34770.3888 . GG hCV9540478 . . . . . . . . . . . . hCV29245634 0.25 0.02742.218 0.2115 . CT + 125 255 9E+ 0 . 0.9883 . CC 05 hCV29245634 . . . . .. . . . . . . hCV16233239 1.25 0.9806 1.583 0.0719 . AA 77 171 0.80.5152 1.2554 0.3376 . hCV16233239 . . . . . . . . . . . . hCV32864821.49 0.8535 2.591 0.1613 . TC + 116 245 0.59 0.2377 1.4739 0.2599 . TThCV3286482 . . . . . . . . . . . . hDV70794769 0.73 0.4152 1.286 0.27650.2084 CC 62 158 0.46 0.2056 1.0179 0.0553 0.0614 hDV70794769 . . . . .. . . . . . . hDV70794769 0.63 0.3509 1.12 0.1148 0.2084 CT 50 84 0.70.3054 1.5824 0.3862 0.0614 hDV70794769 . . . . . . . . . . . .hDV70794769 ref . . . 0.2084 TT 13 15 ref . . . 0.0614 hDV70794769 . . .. . . . . . . . . hDV77026147 2.24 0.4312 11.62 0.3376 . CT + 124 257 00 . 0.9867 . hDV77026147 . . . . . CC . . . . . . . hCV1396435 1.170.8309 1.648 0.3681 0.5028 GG 30 85 0.66 0.3299 1.3053 0.2299 0.1794hCV1396435 . . . . . . . . . . . . hCV1396435 1.01 0.734 1.398 0.93730.5028 GT 75 134 1.05 0.567 1.942 0.8783 0.1794 hCV1396435 . . . . . . .. . . . . hCV1396435 ref . . . 0.5028 TT 20 38 ref . . . 0.1794hCV1396435 . . . . . . . . . . . . hDV70820190 1.19 0.9331 1.527 0.1589. GG 79 178 0.78 0.4957 1.2255 0.2805 . hDV70820190 . . . . . . . . . .. . Above analysis adjusted for sex and age.

TABLE 8 Recurrent VT HR HR Primary VT 95% 95% OR OR EF- HW Cl Cl P- GE-Odds 95% 95% FECT (con- GE- EVE- TO- lo- up- va- P_ EVE- TO- NO Ra- ClCl LA- Var- Prob P_ trol) NO_ NTS_ TAL_ HR_ wer_ per_ lue_ DF2_ Ref NTS_TAL_ SNP rs # Gene MODE TYPE Strata tio lower upper BEL iable ChiSq DF2pExact ALL ALL ALL ALL ALL ALL ALL ALL geno ALL ALL rs3820059 C1orf114GEN AG All 1.127 1.027 1.237 GEN GEN 0.0119 0.00364 0.0353 AG 248 16331.11 0.919 1.335 0.2836 0.0095 GG 199 1459 HET rs3820059 C1orf114 GEN AAAll 1.228 1.072 1.408 GEN GEN 0.0031 0.00364 0.0353 AA 101 508 1.451.141 1.843 0.0024 0.0095 GG 199 1459 HOM rs3820059 C1orf114 ADD A All1.113 1.045 1.186 ADD ADD 0.0009 . 0.0353 0.0095 GG 199 1459 rs3820059Clorf114 DOM AG + All 1.149 1.053 1.255 DOM DOM 0.0019 . 0.0353 AG + 3492141 1.19 0.998 1.415 0.0521 0.0095 GG 199 1459 A AA rs3820059 C1orf114REC AA All 1.155 1.017 1.313 REC REC 0.0264 . 0.0353 AA 101 508 1.451.141 1.843 0.0024 0.0095 GG 199 1459 rs6025 F5 GEN AG All 3.567 3.0474.176 GEN GEN <.0001 0 0.0475 AG 127 580 1.53 1.258 1.871 <.0001 <.0001GG 429 3072 rs6025 F5 GEN AA All 5.412 2.353 12.446 GEN GEN <.0001 00.0475 AA 7 27 1.73 0.817 3.647 0.1522 <.0001 GG 429 3072 HOM rs6025 F5ADD A All 3.423 2.944 3.98 ADD ADD <.0001 . 0.0475 <.0001 GG 429 3072rs6025 F5 DOM AG + All 3.62 3.1 4.228 DOM DOM <.0001 . 0.0475 AG + 134607 1.54 1.27 1.874 <.0001 <.0001 GG 429 3072 AA AA rs6025 F5 REC AA All4.768 2.074 10.963 REC REC 0.0002 . 0.0475 AA 7 27 1.73 0.817 3.6470.1522 <.0001 GG 429 3072 rs4262503 LOC730144/ GEN CT All 0.817 0.7180.928 GEN GEN 0.0019 0.00294 0.258 CT 73 437 1.14 0.892 1.462 0.29130.0072 TT 462 3106 LOC100505872 HET rs4262503 LOC730144/ GEN CC All1.468 0.834 2.582 GEN GEN 0.1832 0.00294 0.258 CC 8 27 2.93 1.454 5.8910.0026 0.0072 TT 462 3106 LOC100505872 HOM rs4262503 LOC730144/ ADD CAll 0.87 0.774 0.979 ADD ADD 0.0209 . 0.258 0.0072 TT 462 3106LOC100505872 rs4262503 LOC730144/ DOM CT + All 0.837 0.739 0.949 DOM DOM0.0055 . 0.258 CT + 81 464 1.22 0.959 1.539 0.1059 0.0072 TT 462 3106LOC100505872 CC CC rs4262503 LOC730144/ REC CC All 1.508 0.858 2.653 RECREC 0.1537 . 0.258 CC 8 27 2.93 1.454 5.891 0.0026 0.0072 TT 462 3106LOC100505872 rs627530 STK11|P/ GEN CT All 1.094 0.924 1.295 GEN GEN0.2963 0.00378 3.57E− CT 44 260 1.21 0.891 1.65 0.2195 0.0259 TT 5103372 OBSL1 HET 11 rs627530 STK11|P/ GEN CC All 2.998 1.527 5.885 GEN GEN0.0014 0.00378 3.57E CC 8 26 2.4 1.192 4.831 0.0143 0.0259 TT 510 3372OBSL1 HOM 11 rs627530 STK11|P/ ADD C All 1.207 1.04 1.401 ADD ADD 0.0133. 3.57E 0.0259 TT 510 3372 OBSL1 11 rs627530 STK11|P/ DOM CT + All 1.1650.99 1.372 DOM DOM 0.0667 . 3.57E CT + 52 286 1.31 0.987 1.747 0.06150.0259 TT 510 3372 OBSL1 CC 11 CC rs627530 STK11|P/ REC CC All 2.9791.518 5.847 REC REC 0.0015 . 3.57E CC 8 26 2.4 1.192 4.831 0.0143 0.0259TT 510 3372 OBSL1 11 rs1800788 GEN TC All 1.231 1.121 1.351 GEN GEN<.0001 0.00001 0.0217 TC 199 1284 1.09 0.911 1.306 0.3433 0.009 CC 2932076 HET rs1800788 GEN TT All 1.307 1.076 1.589 GEN GEN 0.007 0.000010.0217 TT 48 207 1.61 1.187 2.186 0.0022 0.009 CC 293 2076 HOM rs1800788ADD T All 1.189 1.105 1.278 ADD ADD <.0001 . 0.0217 0.009 CC 293 2076rs1800788 DOM TC + All 1.241 1.135 1.356 DOM DOM <.0001 . 0.0217 TC +247 1491 1.16 0.983 1.379 0.0788 0.009 CC 293 2076 TT TT rs1800788 RECTT All 1.214 1.002 1.471 REC REC 0.048 . 0.0217 TT 48 207 1.61 1.1872.186 0.0022 0.009 CC 293 2076 rs2066865 FGG GEN AG All 1.327 1.21 1.456GEN GEN <.0001 0 0.97 AG 229 1528 1.05 0.872 1.263 0.6081 0.0027 GG 2211585 HET rs2066865 FGG GEN AA All 1.939 1.655 2.271 GEN GEN <.0001 00.97 AA 85 406 1.53 1.194 1.971 0.0008 0.0027 GG 221 1585 HOM rs2066865FGG ADD A All 1.366 1.277 1.462 ADD ADD <.0001 . 0.97 0.0027 GG 221 1585rs2066865 FGG DOM AG + All 1.421 1.302 1.551 DOM DOM <.0001 . 0.97 AG +314 1934 1.15 0.966 1.363 0.1174 0.0027 GG 221 1585 A AA rs2066865 FGGREC AA All 1.704 1.464 1.985 REC REC <.0001 . 0.97 AA 85 406 1.53 1.1941.971 0.0008 0.0027 GG 221 1585 rs2066854 FGG GEN AT All 1.314 1.1991.441 GEN GEN <.0001 0 0.849 AT 228 1537 1.03 0.855 1.236 0.7678 0.002TT 225 1607 HET rs2066854 FGG GEN AA All 1.927 1.647 2.254 GEN GEN<.0001 0 0.849 AA 87 415 1.53 1.196 1.964 0.0007 0.002 TT 225 1607 HOMrs2066854 FGG ADD A All 1.359 1.271 1.453 ADD ADD <.0001 . 0.849 0.002TT 225 1607 rs2066854 FGG DOM AT + All 1.41 1.292 1.538 DOM DOM <.0001 .0.849 AT + 315 1952 1.13 0.953 1.342 0.1595 0.002 TT 225 1607 A AArs2066854 FGG REC AA All 1.702 1.463 1.979 REC REC <.0001 . 0.849 AA 87415 1.53 1.196 1.964 0.0007 0.002 TT 225 1607 rs3756008 GEN TA All 1.3491.222 1.489 GEN GEN <.0001 0 0.644 TA 257 1751 0.95 0.778 1.165 0.6350.0316 AA 149 1042 HET rs3756008 GEN TT All 1.721 1.517 1.952 GEN GEN<.0001 0 0.644 TT 137 774 1.25 0.993 1.58 0.0578 0.0316 AA 149 1042 HOMrs3756008 ADD T All 1.317 1.238 1.401 ADD ADD <.0001 . 0.644 0.0316 AA149 1042 rs3756008 DOM TA + All 1.444 1.316 1.585 DOM DOM <.0001 . 0.644TA + 394 2525 1.04 0.86 1.254 0.6945 0.0316 AA 149 1042 TT T rs3756008REC TT All 1.44 1.288 1.609 REC REC <.0001 . 0.644 TT 137 774 1.25 0.9931.58 0.0578 0.0316 AA 149 1042 rs925451 F11 GEN AG All 1.36 1.233 1.5GEN GEN <.0001 0 0.0947 AG 259 1719 1.02 0.838 1.252 0.815 0.0283 GG 1511096 HET rs925451 F11 GEN AA All 1.747 1.537 1.985 GEN GEN <.0001 00.0947 AA 129 725 1.33 1.05 1.681 0.0179 0.0283 GG 151 1096 HOM rs925451F11 ADD A All 1.328 1.248 1.413 ADD ADD <.0001 . 0.0947 0.0283 GG 1511096 rs925451 F11 DOM AG + All 1.455 1.327 1.596 DOM DOM <.0001 . 0.0947AG + 388 2444 1.11 0.918 1.338 0.2834 0.0283 GG 151 1096 A AA rs925451F11 REC AA All 1.462 1.304 1.64 REC REC <.0001 . 0.0947 AA 129 725 1.331.05 1.6181 0.0179 0.0283 GG 151 1096 rs3822057 F11 GEN AC All 0.7850.707 0.871 GEN GEN <.0001 0 0.514 AC 269 1740 0.84 0.694 1.011 0.06460.0042 CC 184 1072 HET rs3822057 F11 GEN AA All 0.6 0.53 0.679 GEN GEN<.0001 0 0.514 AA 86 734 0.65 0.505 0.842 0.0011 0.0042 CC 184 1072 HOMrs3822057 F11 ADD A All 0.775 0.729 0.824 ADD ADD <.0001 . 0.514 0.0042CC 184 1072 rs3822057 F11 DOM AC + All 0.72 0.652 0.794 DOM DOM <.0001 .0.514 AC + 355 2474 0.78 0.656 0.937 0.0073 0.0042 CC 184 1072 AA AArs3822057 F11 REC AA All 0.703 0.633 0.779 REC REC <.0001 . 0.514 AA 86734 0.65 0.505 0.842 0.0011 0.0042 CC 184 1072 rs2036914 F11 GEN TC All0.755 0.683 0.835 GEN GEN <.0001 0 0.476 TC 262 1684 0.9 0.747 1.0790.252 0.0359 CC 201 1238 HET rs2036914 F11 GEN TT All 0.586 0.517 0.664GEN GEN <.0001 0 0.476 TT 77 631 0.71 0.544 0.921 0.01 0.0359 CC 2011238 HOM rs2036914 F11 ADD T All 0.764 0.719 0.813 ADD ADD <.0001 .0.476 0.0359 CC 201 1238 rs2036914 F11 DOM TC + All 0.701 0.638 0.77 DOMDOM <.0001 . 0.476 TC + 339 2315 0.85 0.711 1.008 0.0611 0.0359 CC 2011238 TT TT rs2036914 F11 REC TT All 0.696 0.624 0.776 REC REC <.0001 .0.476 TT 77 631 0.71 0.544 0.921 0.01 0.0359 CC 201 1238 rs3756011 F11GEN AC All 1.347 1.218 1.489 GEN GEN <.0001 0 0.391 AC 258 1730 1.010.823 1.247 0.9046 0.0344 CC 136 994 HET rs3756011 F11 GEN AA All 1.7751.566 2.011 GEN GEN <.0001 0 0.391 AA 147 827 1.3 1.026 1.637 0.02950.0344 CC 136 994 HOM rs3756011 F11 ADD A All 1.334 1.254 1.419 ADD ADD<.0001 . 0.391 0.0344 CC 136 994 rs3756011 F11 DOM AC + All 1.459 1.3281.604 DOM DOM <.0001 . 0.391 AC + 405 2557 1.1 0.906 1.336 0.3371 0.0344CC 136 994 A AA rs3756011 F11 REC AA All 1.482 1.329 1.653 REC REC<.0001 . 0.391 AA 147 827 1.3 1.026 1.637 0.0295 0.0344 CC 136 994rs2289252 F11 GEN TC All 1.381 1.249 1.527 GEN GEN <.0001 0 0.817 TC 2571739 1 0.807 1.226 0.9634 0.032 CC 134 974 HET rs2289252 F11 GEN TT All1.807 1.593 2.049 GEN GEN <.0001 0 0.817 TT 144 814 1.29 1.017 1.630.0354 0.032 CC 134 974 HOM rs2289252 F11 ADD T All 1.348 1.267 1.435ADD ADD <.0001 . 0.817 0.032 CC 134 974 rs2289252 F11 DOM TC + All 1.4921.357 1.64 DOM DOM <.0001 . 0.817 TC + 401 2553 1.08 0.891 1.318 0.42250.032 CC 134 974 TT TT rs2289252 F11 REC TT All 1.485 1.331 1.657 RECREC <.0001 . 0.817 TT 144 814 1.29 1.017 1.63 0.0354 0.032 CC 134 974rs2281390 LOC642074/ GEN TG All 1.132 1.028 1.245 GEN GEN 0.0113 0.027350.0129 TG 154 1100 0.89 0.742 1.079 0.2445 0.0318 GG 383 2448 LOC642043HET rs2281390 LOC642074/ GEN TT All 0.931 0.729 1.187 GEN GEN 0.56210.02735 0.0129 TT 27 112 1.54 1.043 2.278 0.0298 0.0318 GG 383 2448LOC642043 HOM rs2281390 LOC642074/ ADD T All 1.067 0.986 1.155 ADD ADD0.1086 . 0.0129 0.0318 GG 383 2448 LOC642043 rs2281390 LOC642074/ DOMTG + All 1.109 1.011 1.216 DOM DOM 0.0277 . 0.0129 TG + 181 1212 0.950.8 1.139 0.6074 0.0318 GG 383 2448 LOC642043 TT TT rs2281390 LOC642074/REC TT All 0.898 0.705 1.143 REC REC 0.382 . 0.0129 TT 27 112 1.54 1.0432.278 0.0298 0.0318 GG 383 2448 LOC642043 rs2274736 PTPN21 GEN GA All1.098 1 1.204 GEN GEN 0.0489 0.02063 0.455 GA 245 1597 1.13 0.94 1.3610.1919 0.0308 AA 208 1498 HET rs2274736 PTPN21 GEN GA All 1.207 1.0411.399 GEN GEN 0.0126 0.02063 0.455 GG 77 402 1.42 1.092 1.842 0.00880.0308 AA 208 1498 HOM rs2274736 PTPN21 ADD G All 1.098 1.028 1.173 ADDADD 0.0053 . 0.455 0.0308 AA 208 1498 rs2274736 PTPN21 DOM GA + All1.118 1.024 1.221 DOM DOM 0.013 . 0.455 GA + 322 1999 1.19 0.998 1.4150.0522 0.0308 AA 208 1498 G GG rs2274736 PTPN21 REC GG All 1.151 1.0011.324 REC REC 0.0485 . 0.455 GG 77 402 1.42 1.092 1.842 0.0088 0.0308 AA208 1498 rs2266911 STAG2/ GEN TC Female 0.928 0.815 1.057 GEN GEN 0.26140.50818 TC 5 13 2.74 1.13 6.635 0.0257 0.0163 CC 278 1332 ODZ1 adj ageHET rs2266911 STAG2/ GEN TT Female 0.931 0.687 1.263 GEN GEN 0.6470.50818 TT 67 261 1.3 0.996 1.699 0.0533 0.0163 CC 278 1332 ODZ1 adj ageHOM rs2266911 STAG2/ ADD T Female 0.943 0.848 1.048 ADD ADD 0.2766 .0.0163 CC 278 1332 ODZ1 adj age rs2266911 STAG2/ DOM TC + Female 0.9280.819 1.052 DOM DOM 0.2447 . TC + 72 274 1.35 1.042 1.751 0.0232 0.0163CC 278 1332 ODZ1 TT adj age TT rs2266911 STAG2/ REC TT Female 0.9540.706 1.291 REC REC 0.7616 . TT 67 261 1.29 0.986 1.679 0.0639 0.0163 CC278 1332 ODZ1 adj age rs3765407 LUZP1 GEN GT All 0.958 0.869 1.055 GENGEN 0.3815 0.01959 0.338 GT 165 981 1.2 0.998 1.441 0.0521 0.1515 TT 3722519 HET rs3765407 LUZP1 GEN GG All 1.392 1.08 1.794 GEN GEN 0.01060.01959 0.338 GG 18 128 1.07 0.661 1.725 0.7881 0.1515 TT 372 2519 HOMrs3765407 LUZP1 ADD G All 1.031 0.951 1.118 ADD ADD 0.4595 . 0.3380.1515 TT 372 2519 rs3765407 LUZP1 DOM GT + All 0.994 0.905 1.091 DOMDOM 0.8922 . 0.338 GT + 183 1109 1.19 0.993 1.415 0.06 0.1515 TT 3722519 G G rs3765407 LUZP1 REC GG All 1.409 1.095 1.814 REC REC 0.0077 .0.338 GG 18 128 1.07 0.661 1.725 0.7881 0.1515 TT 372 2519 rs4524 F5 GENCT All 0.77 0.701 0.844 GEN GEN <.0001 0 0.3 CT 159 1185 0.82 0.6810.991 0.0404 0.1197 TT 350 2195 HET rs4524 F5 GEN CC All 0.613 0.5070.741 GEN GEN <.0001 0 0.3 CC 28 175 0.98 0.666 1.439 0.9138 0.1197 TT350 2195 HOM rs4524 F5 ADD C All 0.776 0.722 0.834 ADD ADD <.0001 . 0.30.1197 TT 350 2195 rs4524 F5 DOM CT + All 0.745 0.682 0.814 DOM DOM<.0001 . 0.3 CT + 187 1360 0.84 0.705 1.006 0.058 0.1197 TT 350 2195 C Crs4524 F5 REC CC All 0.677 0.562 0.816 REC REC <.0001 . 0.3 CC 28 1750.98 0.666 1.439 0.9138 0.1197 TT 350 2195 rs2070006 GEN TC All 1.2711.152 1.402 GEN GEN <.0001 0 0.251 TC 265 1756 1.1 0.903 1.348 0.33590.0761 CC 150 1084 HET rs2070006 GEN TT All 1.531 1.348 1.738 GEN GEN<.0001 0 0.251 TT 124 720 1.31 1.036 1.669 0.0244 0.0761 CC 150 1084 HOMrs2070006 ADD T All 1.242 1.167 1.322 ADD ADD <.0001 . 0.251 0.0761 CC150 1084 rs2070006 DOM TC + All 1.337 1.219 1.467 DOM DOM <.0001 . 0.251TC + 389 2476 1.16 0.963 1.404 0.1168 0.0761 CC 150 1084 TT TT rs2070006REC TT All 1.329 1.187 1.487 REC REC <.0001 . 0.251 TT 124 720 1.311.036 1.669 0.0244 0.0761 CC 150 1084 rs4253418 F11 GEN AG All 0.7730.653 0.915 GEN GEN 0.0028 0.01096 0.0809 AG 33 233 0.9 0.633 1.2810.5596 0.0992 GG 506 3321 HET rs4253418 F11 GEN AA All 0.87 0.349 2.165GEN GEN 0.7643 0.01096 0.0809 AA 3 8 3.29 1.058 10.254 0.0397 0.0992 GG506 3321 HOM rs4253418 F11 ADD A All 0.789 0.673 0.926 ADD ADD 0.0036 .0.0809 0.0992 GG 506 3321 rs4253418 F11 DOM AG + All 0.776 0.657 0.916DOM DOM 0.0027 . 0.0809 AG + 36 241 0.96 0.683 1.344 0.8053 0.0992 GG506 3321 AA AA rs4253418 F11 REC AA All 0.887 0.356 2.20 REC REC 0.7968. 0.0809 AA 3 8 3.29 1.058 10.254 0.0397 0.0992 GG 506 3321 rs169713 GENCT All 1.145 1042 1.258 GEN GEN 0.0048 0.01464 0.0383 CT 165 1186 0.850.709 1.029 0.0975 0.1511 TT 338 2143 HET rs169713 GEN CC All 1.1290.917 1.389 GEN GEN 0.2521 0.01464 0.0383 CC 29 171 1.15 0.789 1.6850.4617 0.1511 TT 338 2143 HOM rs169713 ADD C All 1.108 1.028 1.194 ADDADD 0.0075 . 0.0383 0.1511 TT 338 2143 rs169713 DOM CT + All 1.143 1.0441.251 DOM DOM 0.0037 . 0.0383 CT + 194 1357 0.89 0.745 1.06 0.19060.1511 TT 338 2143 CC C C rs169713 REC CC All 1.078 0.878 1.323 REC REC0.4732 . 0.0383 CC 29 171 1.15 0.789 1.685 0.4617 0.1511 TT 338 2143rs8176750 ABO GEN AC All 0.93 0.815 1.061 GEN GEN 0.281 0.47492 1 AC 62425 0.95 0.727 1.235 0.6915 0.0912 CC 469 3083 HET rs8176750 ABO GEN AAAll 0.813 0.413 1.602 GEN GEN 0.55 0.47492 1 AA 4 14 2.94 1.094 7.8940.0325 0.0912 CC 469 3083 HOM rs8176750 ABO ADD A All 0.926 0.818 1.049ADD ADD 0.2264 . 1 0.0912 CC 469 3083 rs8176750 ABO DOM AC + All 0.9260.813 1.055 DOM DOM 0.2462 . 1 AC + 66 439 0.99 0.764 1.279 0.92860.0912 CC 469 3083 AA AA rs8176750 ABO REC AA All 0.821 0.417 1.616 RECREC 0.5677 . 1 AA 4 14 2.94 1.094 7.894 0.0325 0.0912 CC 469 3083rs8176750 ABO GEN AC age sex 0.659 0.574 0.757 GEN GEN <.0001 1.032E− AC61 421 0.88 0.672 1.159 0.3685 0.0704 CC 345 2125 among HET 08 Dom (GGorGT) of rs 8176719 rs8176750 ABO GEN AA age sex 0.582 0.295 1.148 GEN GEN0.1183 1.032E− AA 4 14 2.87 1.063 7.725 0.0374 0.0704 CC 345 2125 amongHOM 08 Dom (GGor GT) of rs 8176719 rs8176750 ABO ADD A age sex 0.6720.59 0.765 ADD ADD <.0001 . 0.0704 CC 345 2125 among Dom (GGor GT) of rs8176719 rs8176750 ABO DOM AC + age sex 0.657 0.573 0.752 DOM DOM <.0001. AC + 65 435 0.92 0.707 1.201 0.5458 0.0704 CC 345 2125 AA among AA Dom(GGor GT) of rs 8176719 rs8176750 ABO REC AA age sex 0.632 0.321 1.246REC REC 0.1851 . AA 4 14 2.92 1.086 7.876 0.0337 0.0704 CC 345 2125among Dom (GGor GT) of rs 8176719 rs8176719 ABO GEN GT All 2.023 1.8332.232 GEN GEN <.0001 0 0.156 GT 301 1928 1.21 0.984 1.498 0.0704 0.0549TT 123 952 HET rs8176719 ABO GEN GG All 2.491 2.174 2.853 GEN GEN <.00010 0.156 GG 111 642 1.36 1.052 1.759 0.019 0.0549 123 952 HOM rs8176719ABO ADD G All 1.662 1.556 1.774 ADD ADD <.0001 . 0.156 0.0549 TT 123 952rs8176719 ABO DOM GT + All 2.124 1.934 2.333 DOM DOM <.0001 . 0.156 GT +412 2570 1.25 1.022 1.529 0.0301 0.0549 TT 123 952 GG GG rs8176719 ABOREC GG All 1.646 1.457 1.86 REC REC <.0001 . 0.156 GG 111 642 1.36 1.0521.759 0.019 0.0549 TT 123 952 rs2069946 PROCR GEN CT All 1.304 1.133 1.5GEN GEN 0.0002 0.00076 0.131 CT 55 429 0.79 0.599 1.047 0.1017 0.1585 TT482 3081 HET rs2069946 PROCR GEN CC All 1.344 0.691 2.613 GEN GEN 0.38350.00076 0.131 CC 1 16 0.36 0.05 2.545 0.3048 0.1585 TT 482 3081 HOMrs2069946 PROCR ADD C All 1.282 1.125 1.46 ADD ADD 0.0002 . 0.131 0.1585TT 482 3081 rs2069946 PROCR DOM CT + All 1.305 1.137 1.498 DOM DOM0.0002 . 0.131 CT + 56 445 0.78 0.588 1.023 0.0718 0.1585 TT 482 3081 CCCC rs2069946 PROCR REC CC All 1.305 0.672 2.538 REC REC 0.4319 . 0.131CC 1 16 0.36 0.05 2.545 0.3048 0.1585 TT 482 3081 rs2266911 STAG2/ GENTC male age 2.868 1.089 7.553 GEN GEN 0.0329 0.00558 TC 51 590 0.750.542 1.033 0.0784 0.0881 CC 136 1292 ODZ1 among HET rs2266911 STAG2/GEN TT male age 0.815 0.688 0.967 GEN GEN 0.0189 0.00558 TT 4 77 0.470.175 1.278 0.1399 0.0881 CC 136 1292 ODZ1 among HOM rs2266911 STAG2/ADD T male age 0.909 0.835 0.99 ADD ADD 0.0276 . 0.0881 CC 136 1292 ODZ1among rs2266911 STAG2/ DOM TC + male age 0.845 0.714 0.999 DOM DOM0.0493 . TC + 55 667 0.72 0.524 0.982 0.0384 0.0881 CC 136 1292 ODZ1 TTamong TT rs2266911 STAG2/ REC TT male age 0.81 0.683 0.961 REC REC0.0154 . TT 4 77 0.52 0.192 1.389 0.1901 0.0881 CC 136 1292 ODZ1 amongrs6003 F13B GEN GA All 1.181 1.049 1.33 GEN GEN 0.0059 0.0099 0.00061 GA94 605 1.01 0.81 1.267 0.9087 0.256 AA 421 2802 HET rs6003 F13B GEN GGAll 1.315 0.904 1.914 GEN GEN 0.1523 0.0099 0.00061 GG 12 53 1.62 0.9132.88 0.0988 0.256 AA 421 2802 HOM rs6003 F13B ADD G All 1.172 1.0571.298 ADD ADD 0.0025 . 0.00061 0.256 AA 421 2802 rs6003 F13B DOM GA +All 1.191 1.062 1.335 DOM DOM 0.0028 . 0.00061 GA + 106 658 1.06 0.8551.31 0.6027 0.256 AA 421 2802 GG GG rs6003 F13B REC GG All 1.279 0.881.861 REC REC 0.1976 . 0.00061 GG 12 53 1.62 0.913 2.88 0.0988 0.256 AA421 2802 rs1417121 SDCCAG8/ GEN CG All 1.072 0.978 1.175 GEN GEN 0.13880.00001 0.795 CG 219 1447 1.02 0.854 1.224 0.8117 0.2183 GG 259 1733AKT3 HET rs1417121 SDCCAG8/ GEN CC All 1.47 1.256 1.72 GEN GEN <.00010.00001 0.795 CC 64 377 1.27 0.967 1.672 0.0854 0.2183 GG 259 1733 AKT3HOM rs1417121 SDCCAG8/ ADD C All 1.155 1.08 1.235 ADD ADD <.0001 . 0.7950.2183 GG 259 1733 AKT3 rs1417121 SDCCAG8/ DOM CG + All 1.135 1.0411.239 DOM DOM 0.0043 . 0.795 CG + 283 1824 1.07 0.904 1.266 0.43430.2183 GG 259 1733 AKT3 CC CC rs1417121 SDCCAG8/ REC CC All 1.425 1.2241.659 REC REC <.0001 . 0.795 CC 64 377 1.27 0.967 1.672 0.0854 0.2183 GG259 1733 AKT3 rs12744297 AKT3 GEN GA All 1.107 1.009 1.215 GEN GEN0.0324 0.00055 0.14 GA 259 1577 1.12 0.934 1.34 0.2246 0.2172 AA 2171479 HET rs12744297 AKT3 GEN GG All 1.311 1.138 1.511 GE GEN 0.00020.00055 0.14 GG 59 469 0.89 0.67 1.191 0.4428 0.2172 AA 217 1479 HOMrs12744297 AKT3 ADD G All 1.133 1.063 1.209 ADD ADD 0.0001 . 0.14 0.2172AA 217 1479 rs12744297 AKT3 DOM GA + All 1.148 1.051 1.253 DOM DOM0.0021 . 0.14 GA + 318 2046 1.07 0.899 1.27 0.4531 0.2172 AA 217 1479 GGGG rs12744297 AKT3 REC GG All 1.246 1.09 1.424 REC REC 0.0012 . 0.14 GG59 469 0.89 0.67 1.191 0.4428 0.2172 AA 217 1479 rs3733402 KLKB1 GEN GAAll 0.798 0.721 0.883 GEN GEN <.0001 0 0.592 GA 252 1736 0.88 0.7251.058 0.1696 0.2211 AA 189 1133 HET rs3733402 KLKB1 GEN GG All 0.6740.595 0.763 GEN GEN <.0001 0 0.592 GG 97 685 0.82 0.644 1.051 0.11890.2211 AA 189 1133 HOM rs3733402 KLKB1 ADD G All 0.819 0.77 0.871 ADDADD <.0001 . 0.592 0.2211 AA 189 1133 rs3733402 KLKB1 DOM GA + All 0.7580.689 0.835 DOM DOM <.0001 . 0.592 GA + 349 2421 0.86 0.721 1.027 0.09670.2211 AA 189 1133 GG GG rs3733402 KLKB1 REC GG All 0.777 0.698 0.865REC REC <.0001 . 0.592 GG 97 685 0.82 0.644 1.051 0.1189 0.2211 AA 1891133 rs3087505 KLKB1 GEN AG All 0.85 0.758 0.952 GEN GEN 0.005 0.00010.00568 AG 84 595 0.89 0.705 1.123 0.3252 0.2805 GG 450 2940 HETrs3087505 KLKB1 GEN AA All 0.483 0.317 0.736 GEN GEN 0.0007 0.00010.00568 AA 7 31 1.58 0.75 3.339 0.2284 0.2805 GG 450 2940 HOM rs3087505KLKB1 ADD A All 0.812 0.734 0.898 ADD ADD <.0001 . 0.00568 0.2805 GG 4502940 rs3087505 KLKB1 DOM AG + All 0.82 0.734 0.916 DOM DOM 0.0005 .0.00568 AG + 91 626 0.92 0.735 1.153 0.4718 0.2805 GG 450 2940 A AArs3087505 KLKB1 REC AA All 0.498 0.327 0.757 REC REC 0.0011 . 0.00568 AA7 31 1.58 0.75 3.339 0.2284 0.2805 GG 450 2940 rs2480089 KIF6 GEN CA All0.89 0.811 0.976 GEN GEN 0.0135 0.01339 0.0209 CA 236 1500 1.12 0.9321.344 0.2266 0.2685 AA 225 1576 HET rs2480089 KIF6 GEN CC All 1.0540.912 1.1217 GEN GEN 0.4768 0.01339 0.0209 CC 71 424 1.22 0.931 1.5880.151 0.2685 AA 225 1576 HOM rs2480089 KIF6 ADD C All 0.98 0.918 1.046ADD ADD 0.5491 . 0.0209 0.2685 AA 225 1576 rs2480089 KIF6 DOM CA + All0.921 0.844 1.006 DOM DOM 0.0671 . 0.0209 CA + 307 1924 1.14 0.96 1.3540.135 0.2685 AA 225 1576 CC CC rs2480089 KIF6 REC CC All 1.117 0.9751.281 REC REC 0.1111 . 0.0209 CC 71 424 1.22 0.931 1.588 0.151 0.2685 AA225 1576 rs8176750 ABO GEN AC age sex 0.659 0.574 0.757 GEN GEN <.00011.032E− AC 61 421 0.88 0.672 1.159 0.3685 0.0704 CC 345 2125 among HET08 Dom (GGor GT) of rs 8176719 rs8176750 ABO GEN AA age sex 0.582 0.2951.148 GEN GEN 0.1183 1.032E− AA 4 14 2.87 1.063 7.725 0.0374 0.0704 CC345 2125 among HOM 08 Dom (GGor GT) of rs 8176719 rs8176750 ABO ADD Aage sex 0.672 0.59 0.765 ADD ADD <.0001 . 0.0704 CC 345 2125 among Dom(GGor GT) of rs 8176719 rs8176750 ABO DOM AC + age sex 0.657 0.573 0.752DOM DOM <.0001 . AC + 65 435 0.92 0.707 1.201 0.5458 0.0704 CC 345 2125AA among AA Dom (GGor GT) of rs 8176719 rs8176750 ABO REC AA age sex0.632 0.321 1.246 REC REC 0.1851 . AA 4 14 2.92 1.086 7.876 0.03370.0704 CC 345 2125 among Dom (GGor GT) of rs 8176719 rs8176719 ABO GENGT All 2.023 1.833 2.232 GEN GEN <.0001 0 0.156 GT 301 1928 1.21 0.9841.498 0.0704 0.0549 TT 123 952 HET rs8176719 ABO GEN GG All 2.491 2.1742.853 GEN GEN <.0001 0 0.156 GG 111 642 1.36 1.052 1.759 0.019 0.0549 TT123 952 HOM rs8176719 ABO ADD G All 1.662 1.556 1.774 ADD ADD <.0001 .0.156 0.0549 TT 123 952 rs8176719 ABO DOM GT + All 2.124 1.934 2.333 DOMDOM <.0001 . 0.156 GT + 412 2570 1.25 1.022 1.529 0.0301 0.0549 TT 123952 GG GG rs8176719 ABO REC GG All 1.646 1.457 1.86 REC REC <.0001 .0.156 GG 111 642 1.36 1.052 1.759 0.019 0.0549 TT 123 952 rs3730055 AKT2GEN TC All 0.981 0.868 1.11 GEN GEN 0.7646 0.03411 0.766 TC 86 516 1.220.967 1.537 0.0934 0.2272 CC 436 2935 HET rs3730055 AKT2 GEN TT All1.878 1.161 3.037 GEN GEN 0.0102 0.03411 0.766 TT 6 42 0.88 0.394 1.9740.7595 0.2272 CC 436 2935 HOM rs3730055 AKT2 ADD T All 1.05 0.94 1.173ADD ADD 0.387 . 0.766 0.2272 CC 436 2935 rs3730055 AKT2 DOM TC + All1.017 0.902 1.146 DOM DOM 0.7853 . 0.766 TC + 92 558 1.19 0.95 1.4890.1309 0.2272 CC 436 2935 TT TT rs3730055 AKT2 REC TT All 1.883 1.1653.044 REC REC 0.0098 . 0.766 TT 6 42 0.88 0.394 1.974 0.7595 0.2272 CC436 2935 rs2304167 GP6 GEN CT All 0.907 0.825 0.997 GEN GEN 0.04420.04653 0.744 CT 176 1065 1.18 0.98 1.41 0.081 0.2165 TT 345 2364rs2304167 GP6 GEN CC All 0.818 0.648 1.032 HET GEN 0.0901 0.04653 0.744CC 20 123 1.09 0.688 1.714 0.7231 0.2165 TT 345 2364 GEN rs2304167 GP6ADD C All 0.906 0.838 0.98 HOM ADD 0.0133 . 0.744 0.2165 TT 345 2364rs2304167 GP6 DOM CT + All 0.897 0.818 0.983 ADD DOM 0.0198 . 0.744 CT +196 1188 1.17 0.978 1.39 0.0864 0.2165 TT 345 2364 CC DOM CC rs2304167GP6 REC CC All 0.844 0.67 1.063 REC 0.1489 . 0.744 CC 20 123 1.09 0.6881.714 0.7231 0.2165 TT 345 2364 rs1654416 RDH13/ GEN CT All 0.888 0.8070.976 REC GEN 0.0143 0.01484 1 CT 172 1042 1.17 0.975 1.405 0.09120.2362 TT 348 2379 GP6 GEN rs1654416 RDH13/ GEN CC All 0.798 0.629 1.013HET GEN 0.0641 0.01484 1 CC 18 115 1.01 0.623 1.627 0.9773 0.2362 TT 3482379 GP6 GEN rs1654416 RDH13/ ADD C All 0.89 0.822 0.963 HOM ADD 0.0037. 1 0.2362 TT 348 2379 GP6 ADD rs1654416 RDH13/ DOM CT + All 0.878 0.8010.962 DOM DOM 0.0055 . 1 CT + 190 1157 1.15 0.966 1.377 0.1144 0.2362 TT348 2379 GP6 CC CC rs1654416 RDH13/ REC CC All 0.829 0.654 1.05 REC REC0.1203 . 1 CC 18 115 1.01 0.623 1.627 0.9773 0.2362 TT 348 2379 GP6

TABLE 9 OR OR 95% 95% GENO- AD- Cl Cl Risk SNP hCV # SNP rs # Gene MODETYPE JUST OR Lower upper ProbChiSq P_DF2 allele hCV16282389 rs2726953SCARA5 GEN AG sex age 1.049 0.913 1.205 0.5017 0.0467 A hCV16282389rs2726953 SCARA5 GEN AA sex age 1.34 1.063 1.689 0.0133 0.0467 AhCV16282389 rs2726953 SCARA5 ADD A sex age 1.115 1.01 1.232 0.0318 . AhCV16282389 rs2726953 SCARA5 DOM AG or AA sex age 1.1 0.964 1.254 0.1567. A hCV16282389 rs2726953 SCARA5 REC AA sex age 1.312 1.049 1.639 0.0172. A hCV16282389 rs2726953 SCARA5 GEN AG 1.046 0.91 1.201 0.5266 0.0485 AhCV16282389 rs2726953 SCARA5 GEN AA 1.337 1.061 1.685 0.0139 0.0485 AhCV16282389 rs2726953 SCARA5 ADD A 1.113 1.008 1.23 0.0347 . AhCV16282389 rs2726953 SCARA5 DOM AG or AA 1.097 0.962 1.25 0.1682 . AhCV16282389 rs2726953 SCARA5 REC AA 1.31 1.049 1.637 0.0174 . AhCV9326428 rs687289 ABO GEN AG sex age 2.188 1.891 2.532 <.0001 0 AhCV9326428 rs687289 ABO GEN AA sex age 2.867 2.318 3.546 <.0001 0 AhCV9326428 rs687289 ABO ADD A sex age 1.813 1.639 2.006 <.0001 . AhCV9326428 rs687289 ABO DOM AG or AA sex age 2.322 2.021 2.668 <.0001 .A hCV9326428 rs687289 ABO REC AA sex age 1.834 1.509 2.228 <.0001 . AhCV9326428 rs687289 ABO GEN AG 2.18 1.885 2.521 <.0001 0 A hCV9326428rs687289 ABO GEN AA 2.851 2.307 3.524 <.0001 0 A hCV9326428 rs687289 ABOADD A 1.807 1.634 1.999 <.0001 . A hCV9326428 rs687289 ABO DOM AG or AA2.313 2.014 2.657 <.0001 . A hCV9326428 rs687289 ABO REC AA 1.829 1.5062.221 < .0001 . A hCV15887091 rs2519093 ABO GEN TC sex age 2.135 1.8522.462 <.0001 0 T hCV15887091 rs2519093 ABO GEN TT sex age 1.962 1.4572.642 <.0001 0 T hCV15887091 rs2519093 ABO ADD T sex age 1.766 1.5761.979 <.0001 . T hCV15887091 rs2519093 ABO DOM TC or TT sex age 2.1111.843 2.419 <.0001 . T hCV15887091 rs2519093 ABO REC TT sex age 1.4751.101 1.975 0.0092 . T hCV15887091 rs2519093 ABO GEN TC 2.123 1.8422.447 <.0001 0 T hCV15887091 rs2519093 ABO GEN TT 1.964 1.46 2.641<.0001 0 T hCV15887091 rs2519093 ABO ADD T 1.76 1.571 1.972 <.0001 . ThCV15887091 rs2519093 ABO DOM TC or TT 2.101 1.834 2.406 <.0001 . ThCV15887091 rs2519093 ABO REC TT 1.48 1.106 1.981 0.0084 . T hCV3188439rs4981022 STAB2 GEN GA sex age 0.852 0.741 0.979 0.0242 0.0298 GhCV3188439 rs4981022 STAB2 GEN GG sex age 0.799 0.642 0.995 0.04530.0298 G hCV3188439 rs4981022 STAB2 ADD G sex age 0.88 0.798 0.97 0.0101. G hCV3188439 rs4981022 STAB2 DOM GA or GG sex age 0.841 0.737 0.9590.0096 . G hCV3188439 rs4981022 STAB2 REC GG sex age 0.861 0.699 1.0620.1623 . G hCV3188439 rs4981022 STAB2 GEN GA 0.851 0.741 0.978 0.02320.0285 G hCV3188439 rs4981022 STAB2 GEN GG 0.799 0.642 0.994 0.04440.0285 G hCV3188439 rs4981022 STAB2 ADD G 0.879 0.798 0.969 0.0096 . GhCV3188439 rs4981022 STAB2 DOM GA or GG 0.84 0.737 0.958 0.0091 . GhCV3188439 rs4981022 STAB2 REC GG 0.861 0.699 1.061 0.1606 . GhCV3188431 rs12229292 STAB2 GEN TG sex age 0.994 0.867 1.14 0.93370.0033 T hCV3188431 rs12229292 STAB2 GEN TT sex age 1.563 1.196 2.0420.0011 0.0033 T hCV3188431 rs12229292 STAB2 ADD T sex age 1.121 1.0091.245 0.0332 . T hCV3188431 rs12229292 STAB2 DOM TG or TT sex age 1.0630.933 1.212 0.3598 . T hCV3188431 rs12229292 STAB2 REC TT sex age 1.5671.207 2.034 0.0007 . T hCV3188431 rs12229292 STAB2 GEN TG 1.004 0.8751.151 0.9597 0.0035 T hCV3188431 rs12229292 STAB2 GEN TT 1.564 1.1982.043 0.001 0.0035 T hCV3188431 rs12229292 STAB2 ADD T 1.126 1.014 1.250.0264 . T hCV3188431 rs12229292 STAB2 DOM TG or TT 1.072 0.94 1.2220.2992 . T hCV3188431 rs12229292 STAB2 REC TT 1.562 1.204 2.026 0.0008 .T hCV2485050 rs6575009 GEN GA sex age 1.226 1.003 1.499 0.0465 0.1052 GhCV2485050 rs6575009 GEN GG sex age 1.412 0.601 3.319 0.4282 0.1052 GhCV2485050 rs6575009 ADD G sex age 1.22 1.015 1.466 0.0342 . GhCV2485050 rs6575009 DOM GA or GG sex age 1.234 1.014 1.503 0.0358 . GhCV2485050 rs6575009 REC GG sex age 1.378 0.587 3.236 0.4621 . GhCV2485050 rs6575009 GEN GA 1.23 1.006 1.503 0.0432 0.0993 G hCV2485050rs6575009 GEN GG 1.408 0.6 3.304 0.4315 0.0993 G hCV2485050 rs6575009ADD G 1.222 1.017 1.468 0.0321 . G hCV2485050 rs6575009 DOM GA or GG1.238 1.017 1.506 0.0333 . G hCV2485050 rs6575009 REC GG 1.373 0.5853.22 0.4662 . G hCV27960688 rs4900088 TC2N GEN AG sex age 1.131 0.9731.314 0.1087 0.0034 A hCV27960688 rs4900088 TC2N GEN AA sex age 1.3871.147 1.677 0.0008 0.0034 A hCV27960688 rs4900088 TC2N ADD A sex age1.172 1.067 1.287 0.0009 . A hCV27960688 rs4900088 TC2N DOM AG or AA sexage 1.198 1.039 1.38 0.0127 . A hCV27960688 rs4900088 TC2N REC AA sexage 1.286 1.089 1.518 0.003 . A hCV27960688 rs4900088 TC2N GEN AG 1.1360.978 1.32 0.0951 0.0026 A hCV27960688 rs4900088 TC2N GEN AA 1.396 1.1551.688 0.0006 0.0026 A hCV27960688 rs4900088 TC2N ADD A 1.176 1.071 1.2910.0007 . A hCV27960688 rs4900088 TC2N DOM AG or AA 1.204 1.045 1.3870.0101 . A hCV27960688 rs4900088 TC2N REC AA 1.291 1.094 1.524 0.0025 .A hCV2889230 rs11686314 GEN AG sex age 0.943 0.807 1.103 0.4629 0.029 AhCV2889230 rs11686314 GEN AA sex age 0.511 0.308 0.847 0.0092 0.029 AhCV2889230 rs11686314 ADD A sex age 0.875 0.764 1.003 0.0545 . AhCV2889230 rs11686314 DOM AG or AA sex age 0.902 0.775 1.049 0.1817 . AhCV2889230 rs11686314 REC AA sex age 0.518 0.313 0.857 0.0105 . AhCV2889230 rs11686314 GEN AG 0.941 0.805 1.1 0.4459 0.0316 A hCV2889230rs11686314 GEN AA 0.517 0.312 0.856 0.0104 0.0316 A hCV2889230rs11686314 ADD A 0.875 0.764 1.002 0.054 . A hCV2889230 rs11686314 DOMAG or AA 0.901 0.774 1.048 0.1761 . A hCV2889230 rs11686314 REC AA 0.5240.317 0.867 0.0119 . A hCV31716902 rs12999640 GEN TC sex age 0.938 0.8061.091 0.408 0.086 T hCV31716902 rs12999640 GEN TT sex age 0.619 0.3980.964 0.034 0.086 T hCV31716902 rs12999640 ADD T sex age 0.889 0.7811.012 0.0746 . T hCV31716902 rs12999640 DOM TC or TT sex age 0.906 0.7821.049 0.1866 . T hCV31716902 rs12999640 REC TT sex age 0.63 0.405 0.9790.0399 . T hCV31716902 rs12999640 GEN TC 0.934 0.803 1.087 0.3778 0.092T hCV31716902 rs12999640 GEN TT 0.627 0.403 0.976 0.0386 0.092 ThCV31716902 rs12999640 ADD T 0.888 0.78 1.011 0.072 . T hCV31716902rs12999640 DOM TC or TT 0.903 0.78 1.046 0.1741 . T hCV31716902rs12999640 REC TT 0.638 0.411 0.991 0.0456 . T hCV27484761 rs3783886PTPN21 GEN GA sex age 1.317 1.074 1.615 0.0081 0.0178 G hCV27484761rs3783886 PTPN21 GEN GG sex age 1.566 0.708 3.467 0.2683 0.0178 GhCV27484761 rs3783886 PTPN21 ADD G sex age 1.304 1.085 1.567 0.0047 . GhCV27484761 rs3783886 PTPN21 DOM GA or GG sex age 1.33 1.09 1.623 0.005. G hCV27484761 rs3783886 PTPN21 REC GG sex age 1.515 0.685 3.353 0.3049. G hCV27484761 rs3783886 PTPN21 GEN GA 1.323 1.079 1.622 0.0071 0.0155G hCV27484761 r53783886 PTPN21 GEN GG 1.575 0.712 3.481 0.2619 0.0155 GhCV27484761 r53783886 PTPN21 ADD G 1.309 1.089 1.573 0.004 . GhCV27484761 r53783886 PTPN21 DOM GA or GG 1.336 1.095 1.63 0.0043 . GhCV27484761 r53783886 PTPN21 REC GG 1.523 0.689 3.365 0.2984 . G HW(CON- CON- CON- CON- Ref TROL) CASE TROL CASE TROL CASE TROL SNP hCV #allele pExact Genot cnt cnt Genot cnt cnt Genot cnt cnt hCV16282389 G0.6 A A 201 149 A G 745 706 G G 895 887 hCV16282389 G 0.6 A A 201 149 AG 745 706 G G 895 887 hCV16282389 G 0.6 A A 201 149 A G 745 706 G G 895887 hCV16282389 G 0.6 A A 201 149 A G 745 706 G G 895 887 hCV16282389 G0.6 A A 201 149 A G 745 706 G G 895 887 hCV16282389 G 0.6 A A 201 149 AG 745 706 G G 895 887 hCV16282389 G 0.6 A A 201 149 A G 745 706 G G 895887 hCV16282389 G 0.6 A A 201 149 A G 745 706 G G 895 887 hCV16282389 G0.6 A A 201 149 A G 745 706 G G 895 887 hCV16282389 G 0.6 A A 201 149 AG 745 706 G G 895 887 hCV9326428 G 0.377 A A 326 184 A G 1005 742 G G512 824 hCV9326428 G 0.377 A A 326 184 A G 1005 742 G G 512 824hCV9326428 G 0.377 A A 326 184 A G 1005 742 G G 512 824 hCV9326428 G0.377 A A 326 184 A G 1005 742 G G 512 824 hCV9326428 G 0.377 A A 326184 A G 1005 742 G G 512 824 hCV9326428 G 0.377 AA 326 184 A G 1005 742G G 512 824 hCV9326428 G 0.377 A A 326 184 A G 1005 742 G G 512 824hCV9326428 G 0.377 A A 326 184 A G 1005 742 G G 512 824 hCV9326428 G0.377 A A 326 184 A G 1005 742 G G 512 824 hCV9326428 G 0.377 A A 326184 A G 1005 742 G G 512 824 hCV15887091 C 0.0024 T T 121 79 T C 803 485C C 921 1181 hCV15887091 C 0.0024 T T 121 79 T C 803 485 C C 921 1181hCV15887091 C 0.0024 T T 121 79 T C 803 485 C C 921 1181 hCV15887091 C0.0024 T T 121 79 T C 803 485 CC 921 1181 hCV15887091 C 0.0024 T T 12179 T C 803 485 C C 921 1181 hCV15887091 C 0.0024 T T 121 79 T C 803 485C C 921 1181 hCV15887091 C 0.0024 T T 121 79 T C 803 485 C C 921 1181hCV15887091 C 0.0024 T T 121 79 T C 803 485 C C 921 1181 hCV15887091 C0.0024 T T 121 79 T C 803 485 C C 921 1181 hCV15887091 C 0.0024 T T 12179 T C 803 485 C C 921 1181 hCV3188439 A 0.161 G G 190 206 G A 738 751 AA 919 796 hCV3188439 A 0.161 G G 190 206 G A 738 751 A A 919 796hCV3188439 A 0.161 G G 190 206 G A 738 751 A A 919 796 hCV3188439 A0.161 G G 190 206 GA 738 751 A A 919 796 hCV3188439 A 0.161 G G 190 206G A 738 751 A A 919 796 hCV3188439 A 0.161 G G 190 206 G A 738 751 A A919 796 hCV3188439 A 0.161 G G 190 206 G A 738 751 A A 919 796hCV3188439 A 0.161 G G 190 206 G A 738 751 AA 919 796 hCV3188439 A 0.161G G 190 206 G A 738 751 A A 919 796 hCV3188439 A 0.161 G G 190 206 G A738 751 A A 919 796 hCV3188431 G 0.0155 T T 158 99 T G 732 715 G G 961942 hCV3188431 G 0.0155 T T 158 99 T G 732 715 G G 961 942 hCV3188431 G0.0155 T T 158 99 T G 732 715 G G 961 942 hCV3188431 G 0.0155 T T 158 99T G 732 715 G G 961 942 hCV3188431 G 0.0155 T T 158 99 T G 732 715 G G961 942 hCV3188431 G 0.0155 T T 158 99 T G 732 715 G G 961 942hCV3188431 G 0.0155 T T 158 99 T G 732 715 G G 961 942 hCV3188431 G0.0155 T T 158 99 T G 732 715 G G 961 942 hCV3188431 G 0.0155 T T 158 99T G 732 715 G G 961 942 hCV3188431 G 0.0155 T T 158 99 T G 732 715 G G961 942 hCV2485050 A 0.29 G G 13 9 G A 246 195 A A 1591 1551 hCV2485050A 0.29 G G 13 9 G A 246 195 A A 1591 1551 hCV2485050 A 0.29 G G 13 9 G A246 195 A A 1591 1551 hCV2485050 A 0.29 G G 13 9 G A 246 195 A A 15911551 hCV2485050 A 0.29 G G 13 9 G A 246 195 A A 1591 1551 hCV2485050 A0.29 G G 13 9 G A 246 195 A A 1591 1551 hCV2485050 A 0.29 G G 13 9 G A246 195 A A 1591 1551 hCV2485050 A 0.29 G G 13 9 G A 246 195 A A 15911551 hCV2485050 A 0.29 G G 13 9 G A 246 195 A A 1591 1551 hCV2485050 A0.29 G G 13 9 G A 246 195 A A 1591 1551 hCV27960688 G 0.59 A A 397 306 AG 913 865 G G 537 578 hCV27960688 G 0.59 A A 397 306 A G 913 865 G G 537578 hCV27960688 G 0.59 A A 397 306 A G 913 865 G G 537 578 hCV27960688 G0.59 A A 397 306 A G 913 865 G G 537 578 hCV27960688 G 0.59 A A 397 306A G 913 865 G G 537 578 hCV27960688 G 0.59 A A 397 306 A G 913 865 G G537 578 hCV27960688 G 0.59 A A 397 306 A G 916 865 G G 537 578hCV27960688 G 0.59 A A 397 306 A G 916 865 G G 537 578 hCV27960688 G0.59 A A 397 306 A G 916 865 G G 537 578 hCV27960688 G 0.59 A A 397 306A G 916 865 G G 537 578 hCV2889230 G 0.116 A A 24 43 A G 417 410 G G1408 1303 hCV2889230 G 0.116 A A 24 43 A G 417 410 G G 1408 1303hCV2889230 G 0.116 A A 24 43 A G 417 410 G G 1408 1303 hCV2889230 G0.116 A A 24 43 A G 417 410 G G 1408 1303 hCV2889230 G 0.116 A A 24 43 AG 417 410 G G 1408 1303 hCV2889230 G 0.116 A A 24 43 A G 417 410 G G1408 1303 hCV2889230 G 0.116 A A 24 43 A G 417 410 G G 1408 1303hCV2889230 G 0.116 A A 24 43 A G 417 410 G G 1408 1303 hCV2889230 G0.116 A A 24 43 A G 417 410 G G 1408 1303 hCV2889230 G 0.116 A A 24 43 AG 417 410 G G 1408 1303 hCV31716902 C 0.207 T T 34 50 T C 456 450 C C1358 1252 hCV31716902 C 0.207 T T 34 50 T C 456 450 C C 1358 1252hCV31716902 C 0.207 T T 34 50 T C 456 450 C C 1358 1252 hCV31716902 C0.207 T T 34 50 T C 456 450 C C 1358 1252 hCV31716902 C 0.207 T T 34 50T C 456 450 C C 1358 1252 hCV31716902 C 0.207 T T 34 50 T C 456 450 C C1358 1252 hCV31716902 C 0.207 T T 34 50 T C 456 450 C C 1358 1252hCV31716902 C 0.207 T T 34 50 T C 456 450 C C 1358 1252 hCV31716902 C0.207 T T 34 50 T C 456 450 C C 1358 1252 hCV31716902 C 0.207 T T 34 50T C 456 450 C C 1358 1252 hCV27484761 A 0.0779 0.17 hCV27484761 A 0.07790.17 hCV27484761 A 0.0779 0.17 hCV27484761 A 0.0779 0.17 hCV27484761 A0.0779 0.17 hCV27484761 A 0.0779 0.17 hCV27484761 A 0.0779 0.17hCV27484761 A 0.0779 0.17 hCV27484761 A 0.0779 0.17 hCV27484761 A 0.07790.17

1. A method for determining whether a human's risk for venous thrombosis(VT) is reduced by treatment with an HMG-CoA reductase inhibitor, themethod comprising testing nucleic acid from said human for the presenceor absence of an allele at a polymorphism represented by position 101 ofany one of the nucleotide sequences of SEQ ID NOS:713, 711, 501-710,712, and 714-3098 or its complement, wherein the presence of said alleleindicates said human's risk for VT is reduced by treatment with saidHMG-CoA reductase inhibitor. 2-12. (canceled)
 13. The method of claim 1,wherein said testing comprises nucleic acid amplification. 14.(canceled)
 15. The method of claim 1, wherein said testing is performedusing sequencing, 5′ nuclease digestion, molecular beacon assay,oligonucleotide ligation assay, size analysis, single-strandedconformation polymorphism analysis, or denaturing gradient gelelectrophoresis (DGGE).
 16. The method of claim 1, wherein said testingis performed using an allele-specific method.
 17. The method of claim16, wherein said allele-specific method is allele-specific probehybridization, allele-specific primer extension, or allele-specificamplification.
 18. (canceled)
 19. The method of claim 1, wherein saidhuman is homozygous for said allele.
 20. The method of claim 1, whereinsaid human is heterozygous for said allele.
 21. The method of claim 1,wherein said VT is deep vein thrombosis (DVT).
 22. The method of claim1, wherein said VT is pulmonary embolism (PE).
 23. The method of claim1, wherein said human did not have VT prior to said testing.
 24. Themethod of claim 1, wherein said human had VT prior to said testing andsaid risk is for recurrent VT.
 25. (canceled)
 26. A method fordetermining whether a human has an increased risk for venous thrombosis(VT), comprising testing nucleic acid from said human for the presenceor absence of an allele at a polymorphism represented by position 101 ofany one of the nucleotide sequences of SEQ ID NOS:713, 711, 501-710,712, and 714-3098 or its complement, wherein the presence of said alleleindicates said human has an increased risk for VT.
 27. The method ofclaim 26, wherein said human had VT prior to said testing and said riskis for recurrent VT.
 28. (canceled)
 29. The method of claim 1, furthercomprising administering an HMG-CoA reductase inhibitor to said humanwho has said allele. 30-31. (canceled)
 32. The method of claim 26,further comprising administering a therapeutic agent for treating VT tosaid human who has said allele.
 33. The method of claim 32, wherein saidtherapeutic agent is selected from the group consisting of HMG-CoAreductase inhibitors, anticoagulants such as warfarin, direct thrombininhibitors such as dabigatran, and direct factor Xa inhibitors such asrivaroxaban or apixaban.
 34. A method for reducing risk of venousthrombosis (VT) in a human, comprising administering to said human aneffective amount of an HMG-CoA reductase inhibitor, wherein said humanhas been identified as having an allele at a polymorphism represented byposition 101 of any one of the nucleotide sequences of SEQ ID NOS:713,711, 501-710, 712, and 714-3098 or its complement, wherein the presenceof said allele indicates said human's risk for VT is reduced bytreatment with said HMG-CoA reductase inhibitor.
 35. The method of claim34, wherein said method comprises testing nucleic acid from said humanfor the presence or absence of said allele. 36-37. (canceled)
 38. Adetection reagent for carrying out the method of claim 1, wherein saiddetection reagent is an allele-specific probe or an allele-specificprimer.
 39. A test kit comprising one or more containers containing thedetection reagent of claim 38 and one or more components selected fromthe group consisting of an enzyme, polymerase enzyme, ligase enzyme,buffer, amplification primer pair, dNTPs, ddNTPs, positive controlnucleic acid, negative control, nucleic acid extraction reagent, andinstructions for using said test kit which instruct that the presence ofsaid allele indicates that said risk for VT is reduced by treatment withsaid HMG-CoA reductase inhibitor. 40-42. (canceled)